First-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy

Abstract

ABSTRACThad a high risk of bias due to their study design and were conducted more than 10 years ago and may not be applicable to the standard of care of today.11 Updated evidence to aid treatment decisions in pediatric SAA is, therefore, required.In children, the choice of an appropriate treatment is particularly influenced by the long-term sequelae of the disease and its therapy. Thus, failure-free survival is much more important than survival alone when analyzing the long-term outcomes of children with aplastic anemia. Lack of response, relapse, and clonal evolution are problematic in the IST setting, whereas graft failure, acute and chronic graft-versus-host disease (GVHD), and infectious complications limit the success of BMT. In the present study, we compared the outcomes of children with SAA who received IST or BMT from an MFD as first-line treatment using data from nationwide IST and BMT registries. Methods PatientsBetween 1992 and 2009, a total of 599 consecutive children (younger than 17 years) with acquired SAA underwent BMT from an MFD or received IST as first-line treatment in Japan; 213 patients with an MFD underwent BMT and were registered in the Transplant Registry Unified Management Program (TRUMP) conducted by the Japanese Society for Hematopoietic Cell Transplantation, and 386 patients without an MFD were enrolled in two consecutive prospective multicenter trials (AA-92/97) conducted by the Japanese Childhood Aplastic Anemia Study Group and were initially treated with IST (Table 1). The disease severities were defined as previously reported.12,13 Underlying inherited marrow failure disorders were excluded clinically and by chromosome fragility testing. Marrow cytogenetic studies were performed for all patients, and patients with clonal cytogenetic abnormalities were excluded from this study. Patients with paroxysmal nocturnal hemoglobinuria with clinical symptoms and positive findings on the Ham test/sucrose test were also excluded from this analysis. All treatments were performed after obtaining written informed consent from patients or their parents in accordance with the Declaration of Helsinki. Immunosuppressive therapy and bone marrow transplantation proceduresThe characteristics of the treatment procedures are detailed in Table 2. Three hundred and eighty-six patients were enrolled in the AA-92 (n=84) and AA-97 (n=302) trials, and all the patients were initially treated with a combination of antithymocyte globulin and cyclosporine A. Response to IST and disease relapse were evaluated as previously reported.12 Transplantation data were collected with the use of standardized forms provided by the TRUMP. A total of 213 patients underwent BMT from an MFD as first-line treatment following the local protocols for conditioning regimens and GVHD prophylaxis. Patients who did not reach neutrophil counts >0.5×10 9 /L for 3 consecutive days after transplantation were considered to have had primary graft failure. Patients with initial engraftment in whom absolute neutrophil counts subsequently declin...

How I treat acquired aplastic anemia

“…11,16 However, the advantage in failure-free survival for a young patient with a low neutrophil count declines with increasing age 11 as a result of higher mortality after HLA-identical BMT in patients aged 21 to 40 years or older than 40 years.…”

“…26 There is a strong age effect also after IST, as shown in Figure 5, with survival of 82% and 58% for patients younger than 20 or older than 40 years (A.B., EBMT database, unpublished data); this figure outlines survival after first-line IST and includes salvage therapy with a stem cell transplant for nonresponders. Failure-free or transplant-free survival would be clearly inferior 16 and would favor transplantation, but only in younger patients and only when compared with transplants from matched sibling donors. 11 For this reason, current guidelines recommend IST first-line therapy for all patients without a matched sibling donor.…”

Second allogeneic hematopoietic stem cell transplantation in children with severe aplastic anemia

“…8 In a recent report from our country (Japan), the causes of treatment failure included GF in 12 patients (5.6%) among 213 children with SAA who received HSCT from an MRD between 1992 and 2009. 9 A report from the National Marrow Donor Program showed that the probability of GF at 28 days and 1 year was 10% and 15%, respectively, in 195 children with AA receiving HSCT from an MUD. 10 The only curative approach to overcome GF is a second allograft for patients failing to engraft after the first transplantation.…”

In support of upfront stem cell transplantation as first‐line therapy for paediatric patients with idiopathic severe aplastic anaemia who lack a sibling donor

“…Transplant-related morbidity and mortality were minimal. Although OS following IST has been very good in the paediatric population (83-94%, Dufour et al, 2015a;Yoshida et al, 2014), quality of life is significantly compromised by the restrictions imposed by prolonged cytopenias as a result of slow count recovery (at least 3-4 months in most cases), with the majority of children only achieving partial remissions (Joeng et al, 2014). Dufour et al (2015b) suggested that a change in the paediatric idiopathic SAA treatment algorithm should be instigated with consideration of upfront MUD BMT, when readily available, in place of IST in those without a matched sibling donor.…”