Hematopoietic cell transplantation for aplastic anemia in adults

INTRODUCTION — Aplastic anemia (AA) is a potentially fatal condition, especially if the disease does not respond to immunotherapy and/or progresses to severe pancytopenia. The role of hematopoietic cell transplantation (HCT) in these settings is evolving. As outcomes from HCT improve, more patients may be able to benefit from this approach.

This topic review discusses the use of HCT for adults with severe AA. Separate topic reviews discuss the use of HCT for AA in children and adolescents and other therapies for AA in adults.

●HCT for children with AA – (See "Treatment of acquired aplastic anemia in children and adolescents", section on 'Management'.)

●Other therapies for adults with AA – (See "Treatment of aplastic anemia in adults".)

Discussions of HCT for other bone marrow failure syndromes are also presented separately. (See "Treatment of acquired aplastic anemia in children and adolescents", section on 'Allogeneic HCT' and "Treatment of acquired aplastic anemia in children and adolescents", section on 'Management'.)

OVERVIEW OF APPROACH

Decision to use HCT — The decision to use HCT is made by balancing the likely benefit from HCT versus immunosuppression and/or supportive care, and by assessing the feasibility of transplant (eg, evaluating patient comorbidities and donor availability). (See 'Patient/disease/donor factors' below.)

●For most patients under age 50 years with severe AA (SAA) or very severe AA (vSAA) who have an available matched related or unrelated donor, we suggest proceeding directly to allogeneic HCT rather than pursuing a course of immunosuppressive therapy. The rationale for early transplantation includes improved outcomes with HCT, especially in younger patients, and concerns about the risks of severe infections, excessive blood product transfusions, and late clonal disorders such as myelodysplasia and/or acute leukemia with immunosuppressive therapy. (See "Treatment of aplastic anemia in adults", section on 'Severe AA/very severe AA'.)

Early referral to a transplant center will facilitate timely donor identification and ensure that other pretransplantation issues are addressed. (See 'Pretransplant testing and interventions' below.)

•A matched related donor (typically, a sibling) is preferable to an unrelated donor. However, a matched unrelated donor is an acceptable alternative for patients who do not have a sibling donor or the sibling has comorbid medical conditions. A human leukocyte antigen (HLA)-matched unrelated donor is preferable to a haploidentical related donor. (See 'Preferred donor and preparative regimen' below.)

•Some patients younger than 50 years of age may have comorbidities that preclude transplantation or affect the ability to tolerate transplantation-associated toxicities; additional individuals may not have an available donor. In such cases, other approaches are needed. (See "Treatment of aplastic anemia in adults".)

If a donor cannot be found in a timely manner, the search should continue as long as HCT is considered to be a potentially effective therapy for that patient (eg, as long as the patient could tolerate HCT and the disease does not respond to immunosuppressive therapy). Immunosuppressive therapy sometimes may be used during this period because the search for an unrelated donor may take a long time (eg, four months or more), especially if the patient is unstable.

●For patients ≥50 years of age with SAA, the decision is more nuanced because some older patients can tolerate the toxicities of potentially curative HCT. Thus, HCT or immunotherapy may be appropriate, depending on disease severity and the availability of a donor. This decision is made on a case-by-case basis that considers the degree of cytopenias, life expectancy, and patient preferences.

Patient/disease/donor factors

●Disease severity – HCT generally is reserved for individuals with SAA (eg, bone marrow cellularity <25 percent, bone marrow hypoplasia with absolute neutrophil count [ANC] <500 cells/microL) or vSAA (ANC <200/microL). Patients with SAA or vSAA are more likely to have potentially fatal complications of their disease (eg, infection, bleeding), and their disease is less likely to respond to immunosuppression. In contrast, outcomes with moderate AA are generally better, and use of immunotherapy and/or supportive care may be preferable to the risks of HCT. Additionally, HCT generally is not pursued until any medications that may have induced AA have been discontinued, viral infections have been treated (eg, hepatitis, human immunodeficiency virus [HIV]), and other possible causes of bone marrow aplasia have been addressed (eg, systemic lupus erythematosus, eosinophilic fasciitis, vitamin deficiencies [eg, B12, folate, copper]) (table 1). The evaluation of patients with AA and classification of disease severity is presented in more detail separately. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnostic criteria'.)

●Patient age – Outcomes from HCT historically have been better in younger patients, especially individuals who are ≤20 years of age. However, outcomes have continued to improve in individuals between 20 and 50 years [1]. Thus, HCT is the treatment of choice for patients with SAA <50 years old who have an HLA-matched related donor (typically a sibling) and lack significant medical comorbidities. HCT may also be appropriate for selected patients older than 50 years with excellent performance status who have an available HLA-matched donor. Indications based on age may continue to broaden as transplant outcomes improve.

●Comorbidities – Patient comorbidities may preclude successful HCT. Examples in the setting of AA include infections and/or renal, hepatic, or cardiac dysfunction.

●Donor availability – The availability of an HLA-matched hematopoietic stem cell donor is paramount in the decision to proceed to HCT although experience with alternative donors continues to evolve.

•A related donor is preferable to an unrelated donor with the same degree of HLA matching, due to genetic similarities not assessed by available testing, and closer HLA matching reduces the risks of graft failure and graft-versus-host disease (GVHD) (see 'Complications' below). Another advantage of using an HLA-matched related donor is the greater speed of donor identification. (See 'HLA-matched sibling donor' below.)

•A matched unrelated donor may be appropriate for patients without a suitable related donor, as outcomes with unrelated donors continue to improve. Improvements in donor recruitment, donor identification, molecular HLA typing, GVHD prevention strategies, and/or strategies for pursuing transplantation with haploidentical donors may result in further expansion of the unrelated donor pool. (See 'Overview of HCT considerations' below.)

Evidence for efficacy — Outcomes with HCT appear to be superior to those achieved with immunosuppressive therapy. However, the potential risks and benefits need to be evaluated for each individual patient, as these may differ from individuals participating in clinical trials.

●Patient selection criteria differ among trials and in trials versus a nonclinical trial population.

●Early outcomes may favor immunosuppression, whereas HCT is more likely to be curative.

●Innovations in both HCT and immunosuppression make comparisons with historical controls difficult.

●Patients may have strong preferences for one therapy or the other because the risks and potential benefits are very different.

Randomized trials comparing HCT with immunosuppression in AA are lacking. Two meta-analyses that evaluated available evidence (7955 and 302 patients, respectively) found that overall survival either was greater with HCT or was no different from immunosuppressive therapy [2,3]. Examples of available studies include the following:

●A retrospective review that compared outcomes in 395 individuals with SAA who underwent either HCT (mostly bone marrow from HLA-identical sibling donors, with cyclophosphamide conditioning without radiation) or immunosuppressive therapy (mostly antithymocyte globulin [ATG] from horse) during the 1990s found greater survival at 15 years in those undergoing transplant (69 versus 38 percent) (figure 1) [4]. The relative benefit of HCT versus immunosuppressive therapy was greatest in the youngest children, persisted through age 39, and was less apparent in individuals >40 years, although several individuals over age 40 received a transplant (median age 22 years, range 2 to 54 years). The major causes of death due to HCT were GVHD (44 percent [mostly chronic]) and infection (44 percent). In contrast, most deaths in individuals receiving immunosuppressive therapy were due to bleeding (37 percent) and/or infection (38 percent).

●Evidence from children with AA has shown good long-term survival with HCT. Specific improvements have been associated with reduced incidence and severity of GVHD, higher rates of engraftment, early transplantation before the onset of severe infections, and avoidance of blood product transfusions from the donor. (See "Treatment of acquired aplastic anemia in children and adolescents", section on 'Management'.)

Outcomes with HCT continue to improve with advances in conditioning regimens, infection prophylaxis and treatment, and GVHD prevention. This was illustrated in a report that compared outcomes in 1305 individuals who received a transplant during the decades between 1976 and 1992, during which survival steadily improved [5]. Five-year overall survival increased from 48 percent (1976 to 1980 cohort) to 66 percent (1988 to 1992 cohort). Greater survival was attributed primarily to reduced mortality in the three months immediately following transplantation; institution of cyclosporine a (CSA) for GVHD prevention was the most important intervention.

Among individuals who undergo HCT for SAA, outcomes are better with related donors and with bone marrow rather than peripheral blood as the source of stem cells. (See 'Overview of HCT considerations' below.)

PRETRANSPLANT TESTING AND INTERVENTIONS — Institutional protocols should be followed regarding appropriate pretransplantation testing and interventions. Examples include the following:

Testing — Prior to HCT, patients require testing to eliminate other possible diagnoses and optimize outcomes.

●Eliminate other possible diagnoses – Patients should have testing to eliminate other possible diagnoses (eg, hypoplastic myelodysplastic syndrome, vitamin/mineral deficiency) and other inherited bone marrow failure syndromes (eg, Fanconi anemia). This testing is presented in detail separately. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Differential diagnosis' and "Approach to the adult with pancytopenia" and "Clinical manifestations and diagnosis of Fanconi anemia".)

●Confirm eligibility for HCT – Patients are tested for functional capacity and organ function. (See "Determining eligibility for allogeneic hematopoietic cell transplantation", section on 'Determining eligibility'.)

●Identify active or latent infections – Patients are evaluated for a number of viral, bacterial, and fungal infections, some of which may be asymptomatic. (See "Evaluation for infection before hematopoietic cell transplantation".)

Vaccinations — Immunizations that are given prior to transplant are discussed separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients".)

Transfusion issues — Red blood cell (RBC) and platelet transfusions may cause sensitization to RBC antigens, which in turn may contribute to graft failure (see 'Graft failure/graft rejection' below). Transfusions should be minimized; if they are required, the following is appropriate:

●Never use the potential HCT donor as a source of RBC or platelet donation.

●All transfusions should be leukoreduced or irradiated in order to minimize exposure to donor white blood cells, which may cause transfusion-associated GVHD or febrile nonhemolytic transfusion reactions.

●Cytomegalovirus (CMV)-negative recipients should receive CMV-negative blood products.

OVERVIEW OF HCT CONSIDERATIONS

Preferred donor and preparative regimen — As noted above, a matched related donor (typically, a sibling) is preferable to an unrelated donor, and a human leukocyte antigen (HLA)-matched unrelated donor is preferable to a haploidentical related donor (algorithm 1).

The optimal preparative regimen is unknown, and institutional practices should be followed. Enrollment on a clinical trial is also encouraged.

HLA-matched sibling donor — The optimal donor is an HLA-matched related donor because hematopoietic stem cells from HLA-matched related donors are least likely to be associated with acute or chronic graft-versus-host disease (GVHD). Most donors are HLA-matched at 8 of 8 or 10 of 10 HLA alleles (eg, HLA-A, B, C, Dr, and Dq from both parents). In some instances, a matched unrelated donor may be preferable. (See "Donor selection for hematopoietic cell transplantation", section on 'Matched related donors' and "Donor selection for hematopoietic cell transplantation", section on 'Mismatched related donors'.)

The preparative regimen most frequently used for matched sibling donor transplantation consists of four daily doses of cyclophosphamide (50 mg/kg per day for four days, total dose 200 mg/kg) alternating with three doses of antithymocyte globulin (ATG; total 90 mg/kg).

Matched unrelated donor — If an HLA-matched related donor is not available, we prefer a matched unrelated donor to a haploidentical donor. Typically, a preliminary search is performed that can provide information about the likelihood of finding a donor. This is followed by additional donor testing including more complete HLA typing, evaluation of donor health, and viral serologies. Additional information regarding the search for an unrelated donor, preferred donor characteristics, and alternative donors is presented separately. (See "Donor selection for hematopoietic cell transplantation", section on 'Unrelated donors' and "Donor selection for hematopoietic cell transplantation", section on 'Alternative donors'.)

For matched unrelated donor transplantation, the optimal preparative regimen is unclear. Various strategies have been used, including cyclophosphamide-based conditioning and nonmyeloablative regimens using varying combinations of fludarabine, cyclophosphamide, irradiation, alemtuzumab, and ATG [6-15]. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) has completed a study addressing this issue and found that cyclophosphamide doses of either 50 or 100 mg/kg with total body irradiation (2 Gy), fludarabine, and ATG were optimal [16].

Haploidentical related donor — Evidence is more limited regarding the use of haploidentical related donors in AA (related donors who share one HLA haplotype with the recipient, such as a full or half sibling, parent, or child). However, use of haploidentical donors is increasing and may be appropriate for a patient for whom HCT is indicated and an HLA-matched donor is not available.

Information about haploidentical transplantation is presented separately. (See "HLA-haploidentical hematopoietic cell transplantation".)

Identical twin (syngeneic) donor — Availability of an identical twin donor is extremely rare, and there is limited experience in this setting. Examples of available data include the following:

●A review from the experience of the International Bone Marrow Transplant Registry described the outcome in 40 individuals with AA who received syngeneic HCT between 1964 and 1992 [17]. Twenty-three (58 percent) did not receive pretransplant conditioning. While sustained hematologic recovery was more likely in the patients who underwent conditioning, this was not associated with a survival advantage: actuarial 10-year survival was 78 percent, with significantly greater survival being seen in the patients who did not have conditioning before the first transplant (87 versus 70 percent). Most of the patients (15 of 23) who did not receive conditioning before the first transplant required subsequent transplants in which conditioning was performed.

●A retrospective observational study on behalf of the Severe Aplastic Anemia and Pediatric Diseases Working Parties of the European Group for Blood and Bone Marrow Transplantation (EBMT) reported on the results of 113 syngeneic transplants in 88 patients with AA performed between 1976 and 2009. Transplant practice changed over time, with more individuals in later years receiving ATG as part of pretransplant conditioning, as well as an increasing use of peripheral blood stem cells rather than bone marrow [18]. Results included the following:

•At a median follow-up of 7.3 years, the 10-year estimated overall survival was 93 percent, with five transplant-related deaths (5.7 percent). Overall survival was not influenced by conditioning, graft source, or post-transplant immunosuppression.

•Graft failure occurred in 32 percent of the transplants. Rates of graft failure were significantly higher in transplants that proceeded without conditioning (64 versus 24 percent in those not receiving or receiving conditioning, respectively) as well as when bone marrow was employed as the source of stem cells (37 versus 16 percent in those receiving bone marrow or peripheral blood stem cell transplants, respectively). Lack of post-transplant immunosuppression showed a trend towards an increased risk of graft failure, while the use of ATG did not have an influence.

When an identical twin is used as a donor, there is no concern regarding GVHD; therefore, peripheral blood can be used as a source of hematopoietic cells. This provides more rapid engraftment than bone marrow.

Preferred stem cell source — For the majority of individuals undergoing HCT for AA, we recommend bone marrow rather than peripheral blood as the source of hematopoietic stem cells. In patients with AA, HCT using bone marrow has been demonstrated to provide excellent outcomes and a lower risk of GVHD (see 'Complications' below). Individuals with AA do not have a malignancy and thus do not require a graft-versus-leukemia effect, which is often correlated with GVHD. One exception may be an identical twin donor; in this setting, hematopoietic cells from peripheral blood may be used because there are not concerns regarding GVHD, and engraftment may be more rapid with peripheral blood-derived cells. (See 'Identical twin (syngeneic) donor' above.)

Donation of bone marrow typically requires anesthesia and may not be acceptable to some unrelated donors. However, we always request bone marrow from unrelated donors, and in our experience, most are willing to provide it.

Bone marrow has not been compared directly with peripheral blood as a source of hematopoietic cells in individuals with AA, but observational studies have demonstrated improved survival with bone marrow. The following examples illustrate the available evidence:

●Outcomes of HCT in 1886 patients who had received a first HLA-identical sibling donor HCT for acquired AA between 1999 and 2009 were reported by the EBMT [19]. A survival advantage of bone marrow over peripheral blood was found in all age groups:

•1 to 19 years: 90 versus 76 percent

•>20 years: 74 versus 64 percent

•>50 years: 69 versus 39 percent

Those who received bone marrow had fewer deaths from GVHD (2 versus 6 percent) and infections (6 versus 13 percent); the rate of graft rejection was similar (1.5 versus 2.5 percent). The rate of chronic GVHD was also lower in those who received bone marrow (11 versus 22 percent). However, individuals who received bone marrow were also younger, had not received radiation in the conditioning regimen, and had a shorter interval between diagnosis and transplantation, all of which may have contributed to improved survival.

●The EBMT also reported outcomes in 1448 patients with acquired AA who had an HCT between 2005 and 2009, when the use of unrelated donors was greater [20]. The strongest predictor of survival was the use of bone marrow rather than peripheral blood as a stem cell source (survival at approximately 10 years, 83 versus 70 percent). This impact of stem cell source exceeded the effects of patient age, interval between diagnosis and HCT, related versus unrelated donor, and use of ATG. The odds ratio (OR) for survival was greater with bone marrow versus peripheral blood regardless of whether the donor was related or unrelated:

•Any donor: OR 2.04 (95% CI 1.62-2.58)

•Sibling donor: OR 1.75 (95% CI 1.26-2.42)

•Unrelated donor: OR 1.47 (95% CI 1.02-2.12)

The overall incidence of GVHD was greater with unrelated donors, but survival was similar between related and unrelated donors after correction for patient age, interval between diagnosis and transplant, stem cell source, use of ATG, and donor and recipient cytomegalovirus (CMV) status.

Additional evidence for the reduced risk of GVHD when bone marrow rather than peripheral blood is used as a source of hematopoietic stem cells comes from a meta-analysis of randomized trials comparing stem cell sources in 1521 individuals with a variety of hematologic malignancies [21]. The hazard ratio (HR) for chronic GVHD in individuals who received bone marrow was 0.72 (95% CI 0.61-0.85) and the HR for extensive GVHD was 0.69 (95% CI 0.54-0.9). There was no difference in overall survival, but survival differences are difficult to extrapolate to patients with AA because the issue of disease relapse does not apply. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Risk factors'.)

Umbilical cord blood has been used as a hematopoietic stem cell source for patients with severe AA with encouraging results in those patients for whom a suitable related or unrelated donor cannot be identified, as well as in those whose disease has not responded to immunosuppressive therapy [22-26]. However, the use of cord blood remains experimental [27,28].

GVHD and infection prophylaxis — Prophylaxis for GVHD and infections are similar to HCT for other conditions.

●GVHD – (See "Prevention of graft-versus-host disease".)

●Infections

•Bacterial – (See "Prevention of infections in hematopoietic cell transplant recipients".)

•Viral – (See "Prevention of viral infections in hematopoietic cell transplant recipients".)

•Fungal – (See "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients".)

RETRANSPLANTATION — Rarely, a patient with graft failure may benefit from retransplantation. This was demonstrated in an individual who developed late graft failure at eight years post-transplant [29]. At that time, bone marrow examination showed that 85 percent of hematopoietic cells were of donor origin. The patient was successfully retransplanted from the same donor.

COMPLICATIONS — For the most part, potential complications of allogeneic HCT for AA include treatment toxicities similar to those of allogeneic HCT in other settings. (See "Early complications of hematopoietic cell transplantation" and "Long-term care of the adult hematopoietic cell transplantation survivor".)

Graft failure/graft rejection — In early studies, a major problem in the use of HCT for AA was the risk of graft failure (also called graft rejection). Multiple factors were thought to contribute to this problem, a major one of which is allosensitization of the recipient through the transfusion of red blood cells (RBCs) and platelets. This provides the rationale for avoiding transfusions for any family member who may be a potential donor. (See 'Transfusion issues' above.)

Reported incidence of graft failure ranges from less than 10 percent to as high as 15 to 20 percent; the risk is greater for individuals who are older, whose disease has not responded to prior immunosuppressive therapy, or who have been heavily transfused [30-34].

Additional interventions to reduce the risk of graft failure may include the following:

●Minimizing any RBC and/or platelet transfusions (see 'Transfusion issues' above)

●Addition of antithymocyte globulin (ATG) to the cyclophosphamide preparative regimen (see 'Preferred donor and preparative regimen' above)

●Infusion of adequate numbers of hematopoietic stem cells (see "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells")

Other risk factors for graft failure are not modifiable:

●Older recipient age

●Presence of antibodies against donor human leukocyte antigens (HLAs) that are unrelated to prior transfusions

Options for individuals who experience graft failure are limited; retransplantation may be an option. (See 'Retransplantation' above.)

Graft-versus-host disease — Graft-versus-host disease (GVHD) is a known complication of allogeneic HCT. For patients with hematologic malignancies, the associated phenomenon of graft-versus-leukemia effect is beneficial. However, patients with AA do not require graft-versus-leukemia effect. The lower rate of GVHD from bone marrow versus peripheral blood provides the rationale for using bone marrow as a source of stem cells. (See 'Preferred stem cell source' above.)

The incidence of GVHD and our approaches to diagnosis and management are presented in separate topic reviews:

●Acute GVHD diagnosis – (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

●Acute GVHD management – (See "Treatment of acute graft-versus-host disease".)

●Chronic GVHD diagnosis – (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

●Chronic GVHD management – (See "Treatment of chronic graft-versus-host disease".)

Late malignancy — A significant long-term problem following HCT for AA has been the development of new malignancies (mostly squamous cell cancer).

●A report that evaluated the risk of secondary malignancy following HCT in 700 patients included 621 patients with AA of various etiologies (eg, hepatitis, drugs, chemicals, or unknown) who received a transplant between 1970 and 1993 [35]. There were 23 malignancies (3 percent), 18 of which (78 percent of malignancies) were solid tumors (17 squamous cell cancers, one mucoepidermoid carcinoma). The remaining five were post-transplant lymphoproliferative disorders or acute lymphoblastic leukemia. The peak incidence of squamous cell cancers was between 5 and 20 years post-transplant. Lymphoid malignancies peaked within the first year and did not occur beyond one year.

●In a review from the International Bone Marrow Transplant Registry that included 1029 individuals with AA who received a transplant between 1980 and 1993, there was one case of cancer in the two years following transplantation [36].

Additional long-term studies are required to fully characterize the risks and types of late malignancy.

Other late complications — Common late complications following HCT for AA include a variety of chronic conditions. In a series of 37 individuals transplanted between 1975 and 1996 who were followed for approximately 17 years, chronic health problems were similar to age- and sex-matched controls, with the exception of greater frequency in HCT survivors of cataracts and endocrine problems such as short stature, hypothyroidism, and gonadal dysfunction [37]. Other common medical problems following HCT, including cardiovascular disease, iron overload, and bone health, and an approach to their management is presented separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor".)

SURVIVAL AND QUALITY OF LIFE — Overall survival following HCT for AA continues to improve, especially for those who survive the early post-transplant period and those using unrelated donors.

The following studies illustrate survival rates and causes of death:

●A review from the International Bone Marrow Transplant Registry evaluated the survival and causes of death in 1029 patients with AA who received a transplant between 1980 and 1993, and who were alive and free of AA for at least two years after their HCT [36]. At a median follow-up of 11 years, 60 of these patients had died (5.8 percent). The causes of death were:

•Graft-versus-host disease (GVHD) – 38 patients (63 percent)

•Infection without GVHD – 7 patients (12 percent)

•Organ failure (liver, cardiac, pulmonary, renal) – 5 patients (8 percent)

•Other (hemorrhage, interstitial pneumonia, drug reaction, miscellaneous) – 7 patients (12 percent)

The major risk factors for late death were prolonged interval between diagnosis and transplant, acute GVHD, and chronic GVHD. Of those who had reached their sixth year post-transplant for AA, survival was similar to the age-adjusted general population. A Karnofsky performance status of 90 or greater (table 2) was seen in 88 percent of individuals at the last contact, which was better than those who received a transplant for hematologic malignancies. These long-term survival rates were significantly better than those for patients in the same series who underwent HCT for leukemia (mortality at seven years, 6 versus 12 percent).

●In a series of 94 consecutive patients who received a transplant for AA at the Fred Hutchinson Cancer Research Center in Seattle who were followed for a median of six years (age range 2 to 59 years), overall survival was 88 percent [38]. Improved outcomes compared with historical controls were attributed to the use of antithymocyte globulin (ATG) with cyclosporin in the conditioning regimen (figure 2). (See 'Preferred donor and preparative regimen' above.)

●Survival and quality of life in individuals ≥40 years of age were reported in a series of 23 consecutive patients between 40 to 68 years who received HCT from a human leukocyte antigen (HLA)-identical sibling [39]. Approximately one-half of the patients had received immunosuppressive therapy prior to HCT. At a median follow-up of approximately nine years, overall survival was 65 percent for the entire group (79 percent for those who were free of a documented infection within one month before HCT conditioning was started). All of the long-term survivors were in complete remission with normal blood counts. No deaths occurred beyond day 223 after HCT.

●The effect of recipient age on post-HCT survival has been shown in a report from the British Society for Blood and Marrow Transplantation, which evaluated overall survival in 155 patients who received a transplant for AA [40]. Overall survival at five years was better in those <40 years than those >40 years (87 versus 75 percent). Although there were only 10 patients >50 years of age, five-year survival in this group was 90 percent. There were no additional deaths in any age group after approximately four years. (See 'Patient/disease/donor factors' above.)

These survival rates appear to be comparable to survival rates after immunosuppressive therapy for severe AA. (See "Treatment of aplastic anemia in adults", section on 'Prognosis'.)

Quality of life was evaluated in 212 patients who were alive at least two years after HCT for AA and followed for up to 26 years [41]. The median age at the time of transplantation was 18 years, and the oldest patient was 42 years old. At least one-half of the patients preserved or regained the ability to become pregnant or father a child. Patients rated their quality of life as excellent and symptoms as minimal or mild. In another study that used a self-assessment questionnaire in 37 patients <21 years old who underwent HCT for severe AA between 1975 and 1996 and were alive ≥3 years post-transplant, there were no differences in overall health status, psychosexual function, educational achievement, employment history, or personal income compared with age- and sex-matched controls [37].

INVESTIGATIONAL STRATEGIES — Investigation of other approaches that might improve HCT outcomes or expand the available donor pool are ongoing. As an example, a study evaluated the outcomes in 330 patients according to the length of the donor white blood cell telomeres (the protective caps at the ends of chromosomes that shorten as an individual ages) [42]. Of interest, those who received hematopoietic cells with longer telomeres had better five-year survival (56 versus 40 percent). The association remained significant after adjusting for donor age, HLA compatibility, and a variety of other donor and recipient factors; the mechanism remains unknown [43]. Measurement of telomere length remains investigational.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone marrow failure syndromes".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Allogeneic bone marrow transplant (The Basics)")

SUMMARY AND RECOMMENDATIONS

●The decision to use hematopoietic cell transplantation (HCT) is made by balancing the likely benefit from HCT versus immunosuppression or supportive care alone and the potential complications of each approach. (See 'Overview of approach' above.)

•For most patients under age 50 years with severe aplastic anemia (SAA) or very severe aplastic anemia (vSAA) who have an available donor, we suggest proceeding directly to allogeneic HCT rather than pursuing a course of immunosuppressive therapy (Grade 2C). (See 'Decision to use HCT' above.)

•Some patients younger than 50 years of age may have comorbidities that preclude transplantation or affect the ability to tolerate transplantation-associated toxicities; additional individuals may not have an available donor. (See 'Patient/disease/donor factors' above.)

•For patients ≥50 years of age with SAA, the decision is more nuanced because some older patients can tolerate the toxicities of potentially curative HCT. Thus, HCT or immunotherapy may be appropriate, depending on the need to move forward expeditiously and the availability of a donor. This decision is made on a case-by-case basis that considers disease severity, life expectancy, and patient preferences.

●Early referral to a transplant center will facilitate timely donor identification and ensure other that other pretransplantation issues are addressed. A potential HCT donor should never be used as a source of blood products (red blood cells or platelets) for transfusion. Transfusions should be minimized, and all blood products should be leukoreduced and cytomegalovirus compatible. (See 'Pretransplant testing and interventions' above.)

●A matched related donor (typically, a sibling) is preferable to an unrelated donor, and a human leukocyte antigen (HLA)-matched unrelated donor is preferable to a haploidentical related donor. (See 'Preferred donor and preparative regimen' above.)

●For patients with AA who undergo HCT, we recommend bone marrow rather than peripheral blood as the source of hematopoietic stem cells (Grade 1B). (See 'Preferred stem cell source' above.)

●Complications of HCT for AA include graft failure, graft-versus-host disease, and late malignancy. Overall survival continues to improve and is especially good for individuals who survive the early post-transplant period. (See 'Complications' above and 'Survival and quality of life' above.)

●Management of patients with moderate AA and those for whom HCT is not an option is presented separately. (See "Treatment of aplastic anemia in adults".)

ACKNOWLEDGMENT — The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.