Supportive care in severe and very severe aplastic anemia

Bone Marrow Transplantation (2013) 48, 168–173 & 2013 Macmillan Publishers Limited All rights reserved 0268-3369/13 www.nature.com/bmt

REVIEW

Supportive care in severe and very severe aplastic anemia B Ho¨chsmann1, A Moicean2, A Risitano3, P Ljungman4 and H Schrezenmeier1 for the EBMT Working Party on Aplastic Anemia Optimal management of aplastic anemia (AA) is not confined to immediate diagnosis, early decision making and timely initiation of major treatment strategies (immunosuppression or SCT) but also involves supportive treatment as a crucial part of patient care. Patients are threatened by complications of cytopenia. Here, we summarize current recommendations for prevention and early treatment of fungal, bacterial and viral infections, transfusion strategy and iron chelation and assess the evidence basis. In fact, many recommendations for patients with AA are not based on randomized studies in AA itself, but they are deduced from other conditions with similar severity of cytopenia. Prevention and treatment of complications like hemorrhage, bacterial and fungal infections and of secondary events like alloimmunization to blood products and iron overload have a significant impact on the prognosis of AA patients and need to be carefully observed in daily practice. More controlled studies on supportive care should be performed in this rare disease. Bone Marrow Transplantation (2013) 48, 168–173; doi:10.1038/bmt.2012.220; published online 3 December 2012 Keywords: aplastic anemia; supportive treatment; infection; transfusion; hematopoietic growth factors

INTRODUCTION Survival of patients with aplastic anemia (AA) after both immunosuppression and allogeneic BMT improved substantially over the past 30 years.1 For patients who received immunosuppression, this improvement was not restricted to patients who responded to the specific treatment.2 Remarkably, the prognosis of non-responders to initial immunosuppression also improved substantially over time.2 This is most likely due to the impact of supportive treatment on the overall survival of patients. The individual risk of a patient is mainly determined by the neutrophil, and monocyte counts.2–8 During the past two decades, infection-related mortality and invasive fungal infections decreased.2 However, infections are still the major threat for patients with severe or very severe AA. In the most recently published large clinical trials in AA, the most prevalent complications and the major causes of death still were bacterial and fungal infections.3–5 In the following sections, we will summarize recommendations on the major aspects of supportive treatment in AA, that is, prophylaxis and early treatment of infections, transfusion strategy and treatment of iron overload. PREVENTION OF INFECTIONS BY GENERAL MEDICAL MANAGEMENT OF AA PATIENTS Patients with neutrophil counts p0.5 g/L are at risk of severe infections and management of these patients should therefore be restricted to experienced centers. Most of the following recommendations are based on studies of neutropenic patients in the context of malignant disorders and chemotherapy or SCT and have been adopted for patients with AA. There are no randomized controlled trials on the effects of prophylactic interventions

specifically in the group of AA patients.9 Therefore, it seems reasonable to deduce the recommendations from the large number of randomized controlled clinical trials and the respective meta-analyses, which are available for other neutropenic conditions.10–15 If the patient’s condition allows (ECOG (Eastern Cooperative Oncology Group) performance status 0–2), the evaluation of patients with the possible diagnosis of AA can be performed as an outpatient. Since the 1960s, typical strategies to prevent neutropenic infections were a protective environment, special low-bacterial diet, antibiotic prophylaxis as well as protective closing and isolation but the evidence for the most of them is weak. Several recent studies showed that low-bacterial diet did not significantly reduce the incidence of neutropenic infections, febrile neutropenia, days of antibiotic use, survival and stool colonization by Gram-negative bacilli as well as yeasts in hospitalized patients16–18 and febrile admission in an outpatient setting.19 Thus, the available data do not support the use of a special low-bacteria diet in neutropenic patients.20 Despite the lack of evidence, surveys showed that 43–78% of the hospitals use a special neutropenic diet. We recommend considering basic principles such as: (1) washing hands before preparing food, (2) storing raw meat, fish, chicken in a way that avoids contamination of other food, (3) washing in hot water dishes and cutlery that contact raw meat before placing them in contact with other food, (4) using fresh food without any mold, (5) consumption of pasteurized juices and dairy products, (6) avoiding uncooked meats, seafood, eggs and unwashed fruits and vegetables;20,21 and (7) avoiding raw nuts and dried fruits due to the risk of fungal spores. These recommendations apply in particular to very severe AA patients, while non-severe AA patients can have a standard

1 Institute of Clinical Transfusion Medicine, German Red Cross Blood Transfusion Service, Baden-Wu¨rttemberg—Hessia and University of Ulm, Ulm, Germany; 2Fundeni Clinical Institute, Second Department of Hematology, Bucharest, Romania; 3Department of Biochemistry and Medical Biotechnologies, Federico II University of Naples, Naples, Italy and 4 Department of Hematology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. Correspondence: Dr H Schrezenmeier, Institute of Clinical Transfusion Medicine, German Red Cross Blood Transfusion Service, Baden-Wu¨rttemberg—Hessia and University of Ulm, 89081 Ulm, Germany. E-mail: h.schrezenmeier@blutspende Received 11 October 2012; accepted 11 October 2012; published online 3 December 2012

Supportive treatment for aplastic anemia B Ho¨chsmann et al

169 diet. In cases of severe mucositis, parenteral nutrition may be necessary. Prolonged neutropenia is a major risk factor for acquiring invasive mold infections. There are no evidence-based data supporting avoidance of situations with an increased risk for exposure to molds. Exceptions are well-documented outbreaks of aspergillus infections in patients exposed to sites of construction. Therefore, exposure to construction areas should be avoided. Additionally, it seems reasonable to avoid contact with garbage, compost or potted plants. During hospitalization, protective isolation, including air quality control, prophylactic antibiotics and barrier isolation brought about a significant reduction in an all-cause mortality (relative ratio 0.60 (95% confidence interval 0.50–0.70)) in patients with cancer.15 However, inclusion of prophylactic antibiotics was necessary to show the effect on mortality. Control of air quality and barrier isolation alone (without prophylactic antibiotics) had no significant effect on mortality and overall occurrence of infections.15 Even if no independent effect of barrier precautions and single patient rooms can be proven, they might help to reduce spreading of (multi-) resistant bacteria.22 Thus, barrier isolation and facilities with HEPA filtration as well as one or two bed rooms with en-suite facilities are not imperative but should be used if available. Staff should follow local guidelines regarding clothing and hygienic routines. There should be procedures in place for management of central and peripheral venous catheters. Staff handling venous lines should be taught about the correct practice. Hand washing and rubbing with alcohol-based disinfection solutions must be used before and after handling the patient by the staff and by visitors. Optimal hand hygiene has been shown to be highly effective in reducing neutropenic infections.23,24 As the majority of neutropenic infections are caused by the entry of the microbial flora of the patient into the blood, individual hygiene rules should be explained to the patient. Mucositis and oral lesions are known mechanisms for bacterial entry, resulting in morbidity and mortality of the patients.25 Thus, oral hygiene is an especially important point: soft toothbrushes should be used to avoid causing bleeding and lesions of the mucosa. Additionally, use of antiseptic medical mouth rinse may be reasonable. Early mobilization of the patient should avoid bed sores and guarantee good pulmonary function. Physical exercises are recommended if the patient is well enough. Especially in patients with anemia, training should be adapted to the heart rate. Additionally, passive mobilization and breathing exercises by a physical therapist may be helpful for hospitalized patients who are not able to perform such physical activities. Physical examination (especially for infection and signs of bleeding) and monitoring of vital parameters (blood pressure, heart frequency, temperature) as well as physical parameters like weight, respiration, stools and diuresis have to be evaluated daily in hospitalized patients. PREVENTION AND TREATMENT OF INFECTIONS BY PROPHYLACTIC ANTIBIOTIC OR ANTIMYCOTIC DRUGS Severe AA patients with prolonged periods of severe neutropenia have a high mortality due to mold especially aspergillus infections.2,6,7 Therefore, prophylactic antifungals are often used, but there are no uniform recommendations and no study showing clinical benefit in AA patients. A systematic review and metaanalysis analyzed 64 randomized controlled clinical trials comparing systemic antifungals with placebo, no intervention or other antifungal agents in neutropenic patients after chemotherapy or SCT.26 Antifungal prophylaxis decreased allcause mortality, fungal-related mortality and documented invasive fungal infection in allogeneic hematopoietic stem cell recipients. & 2013 Macmillan Publishers Limited

In acute leukemia patients with and without SCT, there was a significant reduction in fungus-related mortality and documented invasive fungal infection.26 In our opinion, prophylactic antifungals should be used in general for patients with very severe AA.26 Voriconazole or posaconazole appear to be more effective than fluconazole, as they have activity against Aspergillus and also some other mold species. Antifungal prophylaxis should also be considered during the first months after antithymocyte globulin (ATG) therapy and after SCT as long as neutropenia and/or lymphopenia is present. There are no general recommendations for prophylaxis against Pneumocystis jirovecii pneumonia (PJP).9 In transplanted patients, PJP-prophylaxis is routinely given. For patients after immunosuppressive therapy with ATG, the usage of antiviral and PJPprophylaxis depends on the individual center, but many use such prophylaxis until T-cell recovery. Prophylactic antibiotics may prevent Gram-negative sepsis in severe AA patients. In a meta-analysis of 95 randomized controlled clinical trials in afebrile neutropenic cancer patients,11 prophylactic antibiotics reduced mortality.11 Both quinolone antibiotics (such as ciprofloxacin) or a combination of non-absorbable antibiotics (such as neomycin and colistin) can be effective.11 In this metaanalysis, mortality was substantially reduced when analysis was limited to fluoroquinolones.11 However, prophylactic use of fluoroquinolones increased the risk for the development of antibacterial resistance.11 Also, recent data concern about changes in the intestinal microbiota and the emergence of antibiotic resistance caused by antibacterial prophylaxis in neutropenic patientsl.27 The patients most likely to benefit are those with very severe AA, therefore, antibacterial prophylaxis could be considered in this group. The risk of severe infections decreases rapidly with increasing neutrophil counts, and in patients with ANC 40.5 109/L, antibacterial prophylaxis is not recommended. Additionally, some antibiotics (for example beta-lactam antibiotics or sulfa drugs) should be restricted in use because of potential myelosuppressive effects. PROPHYLAXIS AND TREATMENT OF VIRAL INFECTIONS There are only limited data on the risk for antiviral prophylaxis in patients with AA. Patients who undergo allogeneic hematopoietic SCT (HSCT) should follow standard procedures for prevention and treatment of viral infections.28 Many centers use aciclovir in patients who have undergone intensive immunosuppressive therapy with ATG and cyclosporine. CMV-safe blood products should be used in CMV seronegative patients who are or might become candidates for allogeneic HSCT, and it is therefore important to determine the CMV serostatus at diagnosis of such patients. CMV monitoring and preemptive therapy is not warranted outside the HSCT setting. However, CMV and EBV reactivation have been described in AA patients undergoing intensive immunosuppression, with frequencies which may vary according to the specific immunosuppressive regimen.29 Indeed, CMV and EBV reactivation seems increased after alemtuzumab and rabbit ATG, respectively; nucleic acid testing for EBV and CMV DNA might be performed in patients with unexplained fever and antiviral therapy considered. Varicellazoster infections can become severe in severely immunocompromised patients, and antiviral therapy with aciclovir or valaciclovir of either primary or secondary infections (chicken-pox, herpes zoster) is recommended. Influenza is also a potentially severe infection in immunocompromised patients, and therapy with neuraminidase inhibitors (oseltamivir, zanamivir) should be considered in patients with proven influenza. In very severe AA patients and patients early after ATG therapy, postexposure prophylaxis with neuraminidase inhibitors can also be considered. Bone Marrow Transplantation (2013) 168 – 173


170 HEMATOPOIETIC GROWTH FACTORS AS PROPHYLAXIS OF INFECTIONS OR IN COMBINATION WITH IMMUNOSUPPRESSION TO IMPROVE QUALITY OF RESPONSE There is no indication for treatment of AA with growth factors alone.30–33 The addition of G-CSF to triple immunosuppression with ATG, ciclosporin and cortcosteroids accelerates the recovery of neutrophils und reduces the rate of early infections and the length of hospital stay.4,34 Addition of G-CSF does not improve trilineage response, EFS, relapse rate and OS.4,34 One study from Japan comparing immunosuppression with or without G-CSF reported a lower relapse rate in the G-CSF group.5 This was not confirmed in a large European multi-center trial.4 One must also take into account the potential risk that G-CSF increases the incidence of secondary clonal disorders.35,36 There are currently no data to support the routine use of growth factors in AA either alone are as adjunct to immunosuppression.1,31,32

NEUTROPENIC FEVER Fever with neutropenia is an indication for immediate hospitalization. Diagnostic procedures should include careful physical examination, blood cultures and cultures from other relevant sites, while chest X-ray is optional but often useful. However, treatment of infection must be started at once without waiting for culture results. Therefore, local hospital guidelines for treatment of febrile neutropenia should be followed. In addition, patient history and recent medication should also be taken into consideration. In cases of persisting fever or previous or suspected fungal infection diagnostic procedures for invasive fungal infections such as galactomannan testing and CT scan of the chest should be performed. Systemic antifungal therapy should be concerned early in the therapy of fever in neutropenic AA patients. In these cases, CT (computed tomography) scanning of the chest should be performed. The use of short-term G-CSF may result in a temporary increase of neutrophils and may therefore be beneficial. Even though there are no guidelines, it is clear from several studies that prophylactic growth factors do not improve overall results, but growth factors are often given when treating infectious complications of AA. We lack clear evidence to show whether this is beneficial in AA. In life-threatening infections during neutropenia, the use of irradiated granulocyte transfusions should be discussed with the awareness of limited data to support this procedure and the possible side effects. They may have an adjunctive role to bridge the gap between specific treatment and neutrophil recovery.37 A recently published single-center experience demonstrated a strong correlation between response and survival with hematopoietic recovery.37 There has been concern that HLA-alloimmunization will inhibit therapeutic activity of granulocyte concentrates. However, patients with or without HLA alloantibodies did not differ in mean post-transfusion neutrophil count.37

VACCINATION Vaccination strategies for AA patients are not well defined except for patients undergoing transplantation where recommendations are well established.38 There have been concerns about immune activation of different patient cohorts with immune-mediated disorders such as AA patients, patients with autoimmune hematological disorders and patients with rheumatic disorders. The support for these concerns is very limited and is only based on case reports,39–41 while larger controlled studies in rheumatology patients have not shown an increased risk.42,43 On the other hand, the response to vaccination in patients with very severe AA is likely to be poor. In less severely affected patients, vaccinations against pneumococci and influenza can be indicated as the risk/benefit ratio of vaccination is likely to be Bone Marrow Transplantation (2013) 168 – 173

positive. Children with AA should receive their age-appropriate vaccines with the exception of live vaccines (varicella, MMR, live influenza vaccine) while receiving immunosuppression. TRANSFUSION THERAPY Many patients require regular transfusions of RBC concentrates in order to maintain quality of life and physical activity. On the other hand, regular transfusions are associated with the risk of alloimmunization against RBC Ags and iron overload. Platelet transfusion can induce immunization against HLA or human platelet antigens (HPA). Several studies in the 1980s and 1990s have demonstrated a negative impact of the number of pretransplant transfusions on outcome after transplantation.44–46 However, the quality of blood products has improved substantially since these studies were performed. Whether this association is still true when efficiently leukocyte-depleted blood products are used47 is not clear.48 Universal leuko-reduction of blood products has reduced patient alloimmunization,47,49–51 although further studies are needed to confirm the impact on, for example, outcome after SCT. Allosensitization is mostly due to residual leukocytes in transfused blood products, although a study in mice indicates that mHAs on donor erythrocytes may contribute to allosensitisation.48 An erythrocyte-dependent immunization against mHAs is not eliminated by leukocyte depletion.48 A restrictive transfusion policy should be applied, in particular in patients who are candidates for allogeneic BMT.44–46,52 However, a planned transplantation is no reason to withhold an otherwise indicated transfusion. The decision for transfusion should be based on clinical symptoms (signs of hypoxic anemia; signs of hemorrhage).53 A safe Hb level depends on co-morbidities and the physical state of the patient. Therefore, the decision to transfuse RBCs depends on clinical symptoms, Hb value and quality of life. In this context, the transfusion trigger in the most AA patients range between 80–85 g/L. However, patients with cardiac, pulmonary or vascular co-morbidities may require a higher transfusion trigger.53 To avoid hypoxic cell damage, Hb levels p6.0 g/L are obligate transfusion triggers. AA patients should receive prophylactic platelet transfusions in cases of platelets o10 109/L without fever, bleeding signs (including petechial bleeding) or history of major bleeding events.32 Based on data from a single-center study,54 some guidelines even suggest a trigger of 5 109/L for prophylactic transfusion in stable hospitalized patients without bleeding signs (including petechial bleeding).53 This very low transfusion trigger requires regular measurement of platelet count and daily physical examination especially regarding bleeding signs. To allow an immediate therapeutic transfusion in case of major bleeding, availability of platelet concentrates must be assured. AA patients with fever or bleeding signs or history of relevant bleeding (WHO grade 3 or 4 bleeding; for example, cerebral bleeding) should receive prophylactic platelet transfusions if the platelet count is o20 109/L. It can be observed that in many patients bleeding starts if platelet count drops below a certain threshold. This patient–individual threshold based on observation of the clinical course of the patients must be taken into consideration, in particular if a patient experienced a major bleeding complication WHO grade 3 or 4 at a platelet count 45 109/L or in the outpatient setting.55 For invasive procedures, platelet transfusions must be given to achieve the recommended levels.53 Cross-reacting Abs in ATG can bind to platelets and increase platelet consumption. In some patient,s rapid drop of platelet count during ATG infusion can be observed. Therefore, patients should be transfused optimally to achieve a platelet count of 430 109/L before ATG treatment. Immediate therapeutic transfusion is necessary in case of WHO grade 3 or grade 4 bleeding. & 2013 Macmillan Publishers Limited


171 There are no data to show that the use of non-HLA-matched apheresis platelet concentrates is superior to pooled platelet concentrates in non-allosensitized patients.56 In the case of inadequate increments in platelet count after platelet transfusion, screening for HLA-Abs should be performed. If no HLA-Abs can be detected, a screening for HPA Abs should be performed. If HLA-Abs are detected, HLA-matched single-donor apheresis platelet concentrates should be used for the further transfusions. Ideally, the platelet concentrates are identical in HLA-A and HLA-B Ags to the patient. If appropriate platelet donors are not available, the concentrates must be at least negative for the epitopes recognized by the HLA-Abs.57 All blood products must be leukodepleted.32,53 Transfusions from family members should be strictly avoided. There are two reasons for use of irradiated blood products in AA: Irradiation can avoid transfusion-associated GVHD(taGVHD). Data from an animal model suggest that irradiation reduces the risk of allosensitization.32,58 In order to avoid taGVHD, irradiation with 30 Gy is recommended for the following situations:

During ATG treatment and thereafter until lymphocyte count recovers to at least 1 109/L.53,59 During and after other intensive immunosuppressive treatment, for example, fludarabine or alemtuzumab.53 Patients receiving allogeneic SCT.53 Transfusion regimen has to be switched to irradiated blood products at the latest at start of the conditioning.53 Some centers use irradiated blood products in all patients with AA—irrespective of treatment. The aim of this strategy is avoidance of alloimmunization.58,59 A European survey demonstrated substantial heterogeneity in the use of irradiated blood products for AA.59 HLA-matched apheresis platelet concentrates.53 Granulocyte concentrates.32,53

Currently, many centers switch to pathogen-reduced platelet concentrates. The pathogen-reduction treatment seems to be even more effective than irradiation at abrogating leukocyte immune functions.60 In general, there is no need for CMV-negative blood products if universal leukodepletion is applied.61–64 However, some centers give only CMV-negative blood products for patients undergoing HSCT where both the patient and donor are CMV-negative.65 The indications for fresh-frozen plasma in AA patients are the same as those in the general transfusion guidelines.53

IRON CHELATION THERAPY AA patients who are RBC transfusion dependent over a long period of time are at risk of developing iron overload. Iron overload can significantly impact morbidity and mortality of AA.66–69 In the first few months after diagnosis, serum ferritin concentrations and liver iron content do not reach levels that require immediate start of chelation therapy. After initiation of immunosuppressive treatment, one should wait for at least 4–6 months. If the patient responds and achieves remission, it is possible to treat iron overload by venesection. In non-responding patients with ongoing RBC transfusion dependence, start of chelation therapy is recommended when serum ferritin concentration rises above 1000 ng/mL.1,32 This applies in particular to candidates for allogeneic SCT as iron overload is associated with higher transplant-related mortality and worse survival after transplantation.70–73 However, the recommendation with a threshold of 1000 ng/mL has been adopted from other disorders, for example, myelodysplastic syndromes.74,75 There are no studies which establish a treatment threshold specifically & 2013 Macmillan Publishers Limited

for AA. An individual assessment should be performed in each AA patient, taking into account the individual risk of complications of iron overload, the potential adverse events of iron chelators and the expected period with ongoing RBC transfusion dependence. Iron chelation can be performed with desferrioxamine or deferasirox.76 A relatively high incidence of agranulocytosis has been reported with deferiprone.76 Therefore, this is not recommended for AA patients. Only a few studies are available on the use of desferrioxamine in AA.69,77,78 A sub-study of the EPIC trial79 analyzed 116 AA patients with iron overloads who were treated with deferasirox. In this subgroup, the serum ferritin concentration fell significantly during 1 year of treatment and no drug-induced cytopenias were observed.80 Decreases occurred in chelation-naive and previously chelated patients.80

PSYCHOLOGICAL SUPPORT As AA is a rare disease, a careful explanation about the nature of the disease, treatment, prognostic and social impact is important for the patients and their families at the time of diagnosis. The treating physician should allow time for a comprehensive dialog regarding all possible situations that may occur during the treatment, with a special focus on the chronic nature and the potentially slow response of the disease. As cytopenia will persist in a significant proportion of patients, it is important to explain the quality of life besides the cure of the disease as second therapy aim. ‘Rules for a working social life’ are helpful especially in patients with persisting neutropenia to avoid unnecessary reduction in social contacts. A life as normal as possible in most patients is an important support for psychological health. As the diagnosis of AA is a life-changing experience, some patients will need professional psychological support. For some patients, it is helpful to be in contact with other AA patients. Details of patient support groups should be provided.

CONFLICT OF INTEREST The authors declare no conflict of interest

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