The benefits of each are comparable. However, certain subsets of patients derive superior benefit from one or the other.

Allogeneic bone marrow transplantation from human leukocyte antigen (HLA)-matched, related donors is generally accepted as the initial treatment of choice for young patients (less than 20 years old). It results in the complete reconstitution of hematopoiesis, whereas autologous hematopoietic remissions after IST are more susceptible to relapse. The literature indicates that survival rates after ABMT, in patients between the ages of 20 and 40, are comparable to those reported for IST. Better survival rates after ABMT have been attained with improved conditioning regimens and graft-versus-host disease (GVHD) prophylaxis. Best current results demonstrate long-term, event-free survivals with successful allografts on the order of 90 %. Long-term complications after ABMT include GVHD and secondary neoplasms. The role of ABMT from an unrelated donor is being investigated.

For patients older than 40, the generally accepted treatment of choice is IST, which entails the combination of anti-thymocyte globulin and cyclosporin A. A variable proportion of patients (ranging from 20 to 80 %) respond to IST. However, although responses may be frequent, long-term outcome is guarded because some patients may relapse and others may develop a clonal disorder, including myelodysplasia, leukemia, or paroxysmal nocturnal hemoglobinuria. Long-term complications of IST include recurrence and development of clonal myeloid disorders.

In a review on ABMT for the treatment of AA, Horowitz (2000) stated that long-term survival rates ranged from less than 40 to more than 90 % in reported series. These rates have improved over the past 20 years due to significant reductions in GVHD, interstitial pneumonitis, and early transplant-related mortality. Most long-term survivors have excellent performance status. Late complications such as cataracts, thyroid disorders, joint problems, and therapy-related cancers are observed, especially in patients who received radiation for pre-transplant conditioning. Results are best in young patients transplanted with bone marrow from a HLA-identical sibling; early transplantation is appropriate in this group. For older patients or those without an HLA-identical related donor, transplants are better reserved for those who fail to respond to IST.

Kojima and co-workers (2000a) compared the long-term outcome of acquired AA in children treated with IST or ABMT. They recommended ABMT as first-line therapy in pediatric severe AA patients with an HLA-matched family donor. Alternative donor ABMT was recommended as salvage therapy in patients who relapsed or did not respond to initial IST. In a Consensus Conference on the Treatment of Aplastic Anemia, the participants recommended that the number of courses of IST for non-responders before unrelated ABMT consideration to be 1 for children and 2 for adults (Kojima et al, 2000b).

Bone marrow failure (BMF) syndromes entail a broad group of diseases of varying etiologies, in which hematopoeisis is abnormal or completely arrested in one or more cell lines. Bone marrow failure syndromes can be an acquired AA or can be congenital, as part of such syndromes as Fanconi anemia (FA), Diamond Blackfan anemia (DBA), and Schwachman Diamond syndrome. Hematopoietic bone marrow/stem cell transplantation is a therapeutic option for patients with BMF syndromes (Steele et al, 2006, Myers and Davies, 2009, Mehta et al, 2010).

In a report from the Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology on hematopoietic stem cell transplantation (HSCT) for DBA, Mugishima et al (2007) stated that transfusion-dependent DBA patients opt for allogeneic HSCT as curative therapy. These investigators analyzed clinical outcomes of 19 transplanted Japanese patients. Prior to HSCT, 10 patients (53 %) suffered hemosiderosis with organ dysfunction, and all 8 with short stature (42 %) had adverse effects of prednisolone. Median age at the time of HSCT was 56 months. Transplantation sources were 13 bone marrow (6 HLA-matched siblings, and 6 HLA-matched and 1 HLA-mismatched unrelated donors), 5 cord blood (2 HLA-matched siblings and 3 HLA-mismatched unrelated donors), and 1 peripheral blood from haploidentical mother. All 13 patients with BMT and 2 with sibling cord blood transplantation (CBT) had successful engraftment. Of 3 patients who underwent unrelated CBT, 1 died after engraftment, and the other 2 had graft failure but succeeded in a second BMT from an HLA-disparate father and unrelated donor, respectively. One died shortly after haploidentical PBSCT. The 5-year failure-free survival rate after BMT was higher than CBT (100 %: 40 %, p = 0.002). Platelet recovery was slower in 7 unrelated BMT than in 6 sibling BMT (p = 0.030). No other factors were associated with engraftment and survival. These results suggested that allogeneic BMT, but not unrelated CBT, is an effective HSCT for refractory DBA.

In a report from the Italian pediatric group, Locatelli and colleagues (2007) noted that HSCT represents the only treatment potentially able to prevent/rescue the development of marrow failure and myeloid malignancies in patients with FA. While in the past HSCT from an HLA-identical sibling was proven to cure many patients, a higher incidence of treatment failure has been reported in recipients of an unrelated donor (UD) or HLA-partially matched related allograft. These researchers analyzed the outcome of 64 FA patients (age range of 2 to 20 years) who underwent HSCT between January 1989 and December 2005. Patients were transplanted from either an HLA-identical sibling (n = 31), an UD (n = 26), or an HLA-partially matched relative (n = 7). T-cell depletion of the graft was performed in patients transplanted from an HLA-disparate relative. The 8-year estimate of overall survival (OS) for the whole cohort was 67 %; it was 87 %, 40 % and 69 % when the donor was an HLA-identical sibling, an UD, and a mis-matched relative, respectively (p < 0.01). The outcome of recipients of grafts from an UD improved over time, the probability of survival being 10 % and 72 % for patients transplanted before and after 1998, respectively (p < 0.05). The OS probability of children who did or did not receive fludarabine in preparation for the allograft was 86 % and 59 %, respectively (p < 0.05). These data provided support to the concept that a relevant proportion of FA patients undergoing HSCT can now be successfully cured, even in the absence of an HLA-identical sibling, especially if the conditioning regimen includes fludarabine.

Roth and colleagues (2009) stated that paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the clinical triad of corpuscular hemolytic anemia, thrombophilia, and cytopenia. This is caused by an acquired mutation of the PIG (phosphatidylinositol glycan)-A gene of the pluripotent hematopoetic stem cell. This results in a deficiency of GPI (glycosylphosphatidylinositol)-anchors and GPI-anchored proteins on the surface of affected blood cells. Flow cytometry is the standard for diagnosis and measurement of type and size of the PNH clone. Treatment of PNH is mainly symptomatic. Allogeneic BMT is the only curative option in case of severe complications during the course of the diseases.

Li and colleagues (2013) noted that although high-dose cyclophosphamide seems to achieve durable complete remission, there are still concerns about its too much early toxicity. Thus, these researchers designed a clinical study to examine the effects of high-dose cyclophosphamide/anti-thymocyte globulin (ATG) combined with cord blood infusion as first-line therapy for patients with severe AA. Between January 2003 and September 2007, these investigators treated 16 treatment-naive patients with severe AA with cord blood infusion after high-dose cyclophosphamide (50 mg/kg/day × 2) and rabbit ATG (3 mg/kg/day × 5) therapy. Although only 1 patient had durable full donor engraftment, 14 of the enrolled 16 patients had rapid autologous hematopoietic recovery. The median recovery time for neutrophils and platelets was only 23 and 37 days after infusion of cord blood. Of the 15 responding patients, all patients achieved treatment-free remission: 9 patients met the criteria for a complete remission; 6 patients achieved a partial remission. The authors concluded that infusion of cord blood after high-dose cyclophosphamide/ATG resulted in a rapid autologous hematologic recovery and a high response rate in patients with treatment-naive patients with severe AA. They stated that these promising results merit further investigation and confirmation on a larger number of patients.

An UpToDate review on "Aplastic anemia: Prognosis and treatment" (Schrier, 2013) states that "Only a fraction of patients with severe aplastic anemia in first or second complete remission are able to mobilize sufficient stem cells to undergo autologous hematopoietic cell transplantation (HCT). Accordingly, patients with relapsing or resistant disease, who have even fewer mobilizable stem cells than those in remission, are not candidates for autologous HCT". Furthermore, an UpToDate review on "Hematopoietic cell transplantation in aplastic anemia" (Negrin, 2013) recommends the use of allogeneic HCT; it does not mention the use of autologous HCT as a therapeutic option.

UpToDate reviews on "Hematopoietic cell transplantation for Diamond-Blackfan anemia and the myelodysplastic syndromes in children" (Khan, 2013) and "Hematopoietic cell transplantation for idiopathic severe aplastic anemia and Fanconi anemia in children" (Khan and Negrin, 2013) do not mention the use of autologous HCT as a therapeutic option.

An UpToDate review on "Diagnosis and treatment of paroxysmal nocturnal hemoglobinuria" (Rosse, 2013) states that "autologous transplantation is unlikely to be successful because of the difficulty in obtaining sufficient numbers of normal stem cells".

In a Cochrane review, Peinemann and associates (2013) evaluated the effectiveness and adverse events of first-line allogeneic HSCT of HLA-matched sibling donors compared to first-line immunosuppressive therapy including cyclosporine and/or anti-thymocyte or anti-lymphocyte globulin in patients with acquired severe AA. The authors concluded that there are insufficient and biased data that do not allow any conclusions to be made about the comparative effectiveness of first-line allogeneic HSCT of an HLA-matched sibling donor and first-line treatment with cyclosporine and/or anti-thymocyte or anti-lymphocyte globulin (as first-line immunosuppressive therapy). These investigators stated that they were unable to make firm recommendations regarding the choice of intervention for treatment of acquired severe AA.

Williams and colleagues (2014) noted that randomized clinical trials in pediatric AA are rare and data to guide standards of care are scarce. Eighteen pediatric institutions formed the North American Pediatric Aplastic Anemia Consortium (NAPAAC) to foster collaborative studies in AA. The initial goal of NAPAAC was to survey the diagnostic studies and therapies utilized in AA. The survey indicated considerable variability among institutions in the diagnosis and treatment of AA. There were areas of general consensus, including the need for a bone marrow evaluation, cytogenetic and specific fluorescent in-situ hybridization assays to establish diagnosis and exclude genetic etiologies with many institutions requiring results prior to initiation of IST; uniform referral for HSCT as first line therapy if an HLA-identical sibling is identified; the use of first-line IST containing horse anti-thymocyte globulin and cyclosporine A (CSA) if an HLA-identical sibling donor is not identified; supportive care measures; and slow taper of CSA after response. Areas of controversy included the need for telomere length results prior to IST, the time after IST initiation defining a treatment failure; use of hematopoietic growth factors; the preferred rescue therapy after failure of IST; the use of specific hemoglobin and platelet levels as triggers for transfusion support; the use of prophylactic antibiotics; and follow-up monitoring after completion of treatment. The authors concluded that these initial survey results reflected heterogeneity in diagnosis and care amongst pediatric centers and emphasized the need to develop evidence-based diagnosis and treatment approaches in this rare disease.

Aplastic anemia is a disorder characterized by the presence of pancytopenia and a hypo-cellular bone marrow. Acquired pure red cell aplasia (PRCA), a part of a unique form of AA, is a rare condition of profound anemia characterized by the absence of reticulocytes and the virtual absence of erythroid precursors in the bone marrow.

An UpToDate review on "Determining eligibility for allogeneic hematopoietic cell transplantation" (Deeg and Sandmaier, 2014) states that "In general, allo-HCT may be considered in the following settings …. Nonmalignant inherited and acquired marrow disorders – Treatment of sickle cell anemia, beta-thalassemia major, refractory Diamond-Blackfan anemia, myelodysplastic syndrome, idiopathic severe aplastic anemia, paroxysmal nocturnal hemoglobinuria, pure red cell aplasia, Fanconi anemia, amegakaryocytosis, or congenital thrombocytopenia".

Second Hematopoietic Stem Cell Transplantation for Graft Failure in Adult Patients with Severe Aplastic Anemia

Haploidentical Hematopoietic Cell Transplantation for the Treatment of Aplastic Anemia

ElGohary and associates (2020) noted that AA is a serious hematological disorder, which is solely cured by HSCT. Haploidentical HSCT is an emerging modality with encouraging outcomes in several blood conditions. These investigators examined the feasibility and safety of haploidentical HSCT in patients with severe and very severe AA. This was a systematic review and meta-analysis of studies related to haploidentical stem cell transplantation in idiopathic AA investigating rates of successful engraftment, acute GVHD (aGVHD), chronic GVHD (cGVHD), transplant-related mortality (TRM), and post-transplantation viral infections (including cytomegalovirus [CMV]) in patients with AA. The effects of reduced-intensity conditioning (RIC) and non-myeloablative conditioning (NMA), as well as various GVHD prophylaxis regimens on these outcomes were evaluated. A total of 15 studies were identified (577 patients, 58.9 % males); successful engraftment was observed in 97.3 % of patients (95 % CI: 95.9 to 98.7) while grades II to IV aGVHD and cGVHD were reported in 26.6 % and 25.0 %, respectively. The pooled incidence of TRM was 6.7 % per year (95 % CI: 4.0 to 9.4). RIC regimens were associated with higher proportions of successful engraftment (97.7 % versus 91.7 %, p = 0.03) and aGVHD (29.5 % versus 18.7 %, p = 0.008) when compared with NMA regimens with no differences in cGVHD or mortality incidence. When compared with methotrexate (MTX)-containing regimens and other regimens, post-transplant cyclophosphamide-containing regimens reduced the rates of aGVHD (28.6 %, 27.8 %, and 12.8 %, respectively, p = 0.02), CMV viremia (55.7 %, 38.6 %, and 10.4 %, respectively, p < 0.001), and CMV disease in initially viremic patients (2.1 %, 33.0 %, and 0 %, respectively, p < 0.001). The authors concluded that haploidentical HSCT was associated with promising outcomes in terms of successful engraftment and reduced complications. Moreover, these researchers stated that future prospective trials are needed to identify the preferred conditioning regimen, GVHD prophylaxis, and graft source in the setting of haploidentical transplant for AA.

Furthermore, an UpToDate review on "Hematopoietic cell transplantation for aplastic anemia in adults" (2020) states that "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".

Allogeneic Hematopoietic Cell Transplantation for Congenital Dyserythropoietic Anemia

Rangarajan et al (2022) stated that HCT is the sole curative option for congenital dyserythropoietic anemia (CDA), a rare type of hemolytic anemia characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. In a retrospective, multi-center study, these investigators reported the outcomes of children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium centers. Clinical information on HCT and associated outcomes was collected retrospectively using a common questionnaire. Data were analyzed using descriptive statistics and appropriate analysis. A total of 18 patients with CDA who underwent allogeneic HCT between 2002 and 2020 were identified. The majority of patients (n = 13) had CDA type II, and the remainder had either CDA type I (n = 2) or CDA of unknown type (n = 3). Mutations were identified in 7 patients (39 %), including SEC23B in 5, GATA1 in 1, and abnormality of chromosome 20 in 1; 13 patients had evidence of iron overload pre-HCT and received chelation therapy for a median duration of 10 months (range of 2 months to 17 years) pre-HCT. The median age at the time of HCT was 5.5 years (range of 0.7 to 26 years). Donors were HLA-matched (sibling, 4; unrelated, 10) and mismatched (haploidentical, 1; unrelated, 3). Graft sources were bone marrow in 15 patients, umbilical cord blood in 2 patients, or both in 1 patient. Conditioning included busulfan-based myeloablative (67 %), fludarabine-based reduced-intensity (27 %), or non-myeloablative (6 %) regimens; 5 patients developed veno-occlusive disease, and 4 had viral reactivation. The cumulative incidence of acute GVHD was 33 %, and that of chronic GVHD was 22 %; 4 patients (22 %) experienced graft failure; all engrafted following either a 2nd HCT (n = 2) or 3rd HCT (n = 2) but sustained considerable morbidities (3 GVHD, 1 death, 2 viral reactivation). With a median follow-up of 3.2 years (range of 0.6 to 14 years)), the 2-year OS, event-free survival (EFS), and GVHD-free EFS were 88 % (95 % CI: 73 % to 100 %), 65 % (95 % CI: 45 % to 92 %), and 60 % (95 % CI: 40 % to 88 %), respectively. Univariate analysis did not identify any patient- or transplantation-related variables impacting outcomes. The authors concluded that the findings of this study indicated that HCT could be curative for patients with CDA. Strategies such as aggressive chelation, use of pre-conditioning therapy, and early HCT in the presence of a suitable donor before co-morbidities occur are needed to improve engraftment without increasing the risk for toxicity and mortality.

Furthermore, an UpToDate review on “Overview of causes of anemia in children due to decreased red blood cell production” (Narla and Sandoval, 2022) states that “The congenital dyserythropoietic anemias (CDA) are a rare group of disorders that result in anemia caused by ineffective erythropoiesis and multinuclear erythroblasts. Treatment may include splenectomy, interferon alfa, and transfusion in symptomatic patients … Hematopoietic cell transplantation (HCT) is a curative therapy for many malignant and nonmalignant hematologic/immunologic disorders. HCT has been described in 7 patients with CDA. Four had CDA I, two had CDA II, and, in one case, the CDA type was unknown. These 7 patients received hematopoietic stem cells from matched sibling donors, and all successfully engrafted and became transfusion-independent”.

Scope of Policy

This Clinical Policy Bulletin addresses hematopoietic cell transplantation for aplastic anemia and other bone marrow failure syndromes.

Medical Necessity

Experimental and Investigational