Unrelated donor bone marrow transplantation to treat severe aplastic anaemia in children and young adults

Alternative donor bone marrow transplantation (BMT) to treat severe aplastic anaemia (SAA) in children and young adults has been complicated by high rates of graft rejection and severe graft-versus-host disease (GVHD). We hypothesized that increased immunosuppression combined with T-cell depletion of the marrow graft would enable successful use of unrelated donor BMT in this disease. Preconditioning consisted of cytosine arabinoside, cyclophosphamide, and total body irradiation (TBI). T-cell depletion was with the anti-CD3 antibody T10B9. GVHD prophylaxis consisted of cyclosporine A. 28 previously transfused patients were transplanted. Nine donor/recipient pairs were HLA matched. As of 1 January 1996, 15/28 (54%) patients are alive, transfusion independent and well with a range of follow-up of 13 months to 8 years (median 2.75 years). Fatalities include all three patients with non-engraftment and all three patients with grade III/IV GVHD. Other fatalities were due to infections or therapy-related toxicity. The incidence ≥ grade II acute GVHD was 28%. These data show that in children with SAA who have failed immunosuppression, unrelated donor BMT offers a reasonable hope of long-term survival.     

How I manage aplastic anaemia in children

Aplastic anaemia (AA) is a rare heterogeneous condition in children. 15–20% of cases are constitutional and correct diagnosis of these inherited causes of AA is important for appropriate management. For idiopathic severe aplastic anaemia, a matched sibling donor (MSD) haematopoietic stem cell transplant (HSCT) is the treatment of choice. If a MSD is not available, the options include immunosuppressive therapy (IST) or unrelated donor HSCT. IST with horse anti‐thymocyte globulin (ATG) is superior to rabbit ATG and has good long‐term results. In contrast, IST with rabbit ATG has an overall response of only 30–40%. Due to improvements in outcome over the last two decades in matched unrelated donor (MUD) HSCT, results are now similar to that of MSD HSCT. The decision to proceed with IST with ATG or MUD HSCT will depend on the likelihood of finding a MUD and the differing risks and benefits that each therapy provides.     

Leukaemic transformation of donor cells in a patient receiving a second allogeneic bone marrow transplant for severe aplastic anaemia

Allogeneic blood or bone marrow transplantation is a successful treatment for leukaemia and severe aplastic anaemia (SAA). Graft rejection following transplantation for leukaemia is a rare event but leukaemic relapse may occur at varying rates, depending upon the stage of leukaemia at which the transplant was undertaken and the type of leukaemia. Relapse is generally assumed to occur in residual host cells, which are refractory to, or escape from the myeloablative conditioning therapy. Rare cases have been described, however, in which the leukaemia recurs in cells of donor origin. Lack of a successful outcome of blood or bone marrow transplantation for severe aplastic anaemia (SAA), however, is due to late graft rejection or graft-versus-host disease. Leukaemia in cells of donor origin has rarely been reported in patients following allogeneic bone marrow transplantation for SAA. This report describes leukaemic transformation in donor cells following a second allogeneic BMT for severe aplastic anaemia. PCR of short tandem repeats in bone marrow aspirates and in colonies derived from BFUE and CFU-GM indicated the donor origin of leukaemia. Donor leukaemia is a rare event following transplantation for severe aplastic anaemia but may represent the persistence or perturbation of a stromal defect in these patients inducing leukaemic change in donor haemopoietic stem cells.     

Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia

The management of patients with severe aplastic anaemia (SAA) who do not have a matched sibling donor and fail a course of horse anti-thymocyte globulin (h-ATG)/ciclosporin (CsA) is uncertain. Repeated courses of ATG-based immunosuppression are often employed; in children and increasingly in adults, alternative donor haematopoietic stem cell transplantation is an option. We analysed the success rate of retreatment with rabbit ATG (r-ATG)/CsA in 43 patients treated at our institution in the last 5 years; 22 were refractory (20 adults; two children) to h-ATG/CsA-based regimens and 21 (17 adults; four children) had relapsed after h-ATG/CsA-based regimens. The overall response rate was 30% in patients who were refractory to h-ATG and 65% in patients who had relapsed following h-ATG. The 1000-d survival in patients who responded to r-ATG was 90% compared with 65% in non-responders. Six patients developed a clonal haematological disorder; two were responders, two were non-responders and in two the evolution occurred before the response could be assessed at 3 months following r-ATG. Thirteen patients died; three were responders, six were non-responders and four patients died prior to 3 months when response was assessed. In our study, the response rate in refractory patients was inferior to what has been previously reported.     

Sustained trilineage response in a patient with ALG-resistant severe aplastic anaemia after treatment with G-CSF, erythropoietin and cyclosporin A: association of recovery with marked elevation of serum alkaline phosphatase

Summary. Aplastic anaemia is characterized by multilineage bone marrow failure resulting in pancytopenia. We have successfully treated a young woman with severe aplastic anaemia (SAA) who was resistant to antilymphocyte globulin (ALG) and corticosteroids, with a combination therapy consisting of erythropoietin. cyclosporin A and granulocyte-colony stimulating factor (G-CSF). The patient received erythropoietin and CSA for a period of 10 months without success before G-CSF treatment was started. After 6 weeks of G-CSF therapy she responded with a sustained trilineage recovery. This suggests that immunosuppression together with haemopoietic growth factors may be an effective treatment in patients with SAA who are ALG resistant and cannot be treated by BMT.     

Allogeneic stem cell transplantation using alemtuzumab-containing regimens in severe aplastic anemia

Alemtuzumab, a humanized anti-CD52, IgG1 monoclonal antibody, is used to reduce graft-versus- host disease (GVHD) and aid engraftment after allogeneic haemopoietic stem cell transplant (HSCT). Its associated low incidence of GVHD makes it an attractive alternative to anti-thymocyte globulin (ATG) in transplant conditioning regimen for severe aplastic anaemia (SAA). We have reviewed the use of alemtuzumab-based conditioning regimen for HSCT in SAA and show that it results in sustained haematological engraftment, a very low incidence of chronic GVHD without an increase in viral infections. Intriguingly, alemtuzumab appears to induce tolerance post-HSCT with the findings of stable mixed T cell chimerism with full donor myeloid chimerism and the absence of chronic GVHD, and which persist on withdrawal of post-graft immunosuppression. Finally, its low toxicity profile may permit future application of HSCT to older patients with SAA who fail to respond to immunosuppressive therapy.     

Unrelated donor bone marrow transplantation for children with severe aplastic anemia: minimal GVHD and durable engraftment with partial T cell depletion

Both increased graft rejection and increased graft vs host disease (GVHD) remain obstacles to success for unrelated donor (URD) BMT for patients with SAA. Partial T cell depletion (PTCD) may decrease the risk of severe GVHD, while still maintaining sufficient donor T lymphocytes to ensure engraftment. We report on 12 patients with SAA who underwent PTCD URD BMT. All patients had failed medical therapy or relapsed following initial responses, and were transfusion dependent. The median age was 6 years, and there were five males. Donors were matched for four patients, and mismatched for eight. All patients received total body irradiation with either Ara-C or thiotepa and cyclophosphamide. PTCD was accomplished using monoclonal antibody T10B9 or OKT3 and complement. All patients engrafted, with a median time of 18 days to ANC >500. Only one patient had greater than grade II acute GVHD; two patients had limited and one patient extensive chronic GVHD. Nine patients are alive and transfusion independent at a median months post BMT. Three patients died from infection or renal failure. This series suggests that an aggressive immunosuppressive conditioning regimen with PTCD results in successful engraftment and minimal GVHD in pediatric patients with SAA, even with HLA mismatched donors.     

Late graft rejection and second infusion of bone marrow in children with aplastic anaemia

Late graft rejection following allogeneic bone marrow transplantation (BMT) for aplastic anaemia is a significant clinical problem and is associated with a high risk of mortality. We report two children with severe aplastic anaemia (SAA) who developed very late graft rejection 2 years and 4 months and 10 years respectively after allogeneic BMT from HLA-identical siblings. Following a second BMT from their initial donors, engraftment has been sustained in both cases. The patients are alive with full donor chimaerism, 18 and 19 years from initial transplant. These cases illustrate that graft failure can be an extremely late event after allogeneic BMT for SAA, and that long-term sustained engraftment can be achieved in these patients with second BMT from the original donors.     

High-dose peripheral blood stem cell transplant for multitransfused severe aplastic anaemia patients without antithymocyte globulin in the conditioning regimen.

Four multitransfused patients with severe aplastic anaemia (SAA) are described. Two received a BMT after conditioning with cyclophosphamide (Cy) plus antithymocyte globulin (ATG). Both suffered a graft failure (GF) and had a second transplant with PBSC from the original donor. Two other patients received a PBSCT as a first option, with Cy as the only conditioning drug. The four patients received methotrexate (MTX) and cyclosporine (CYA) as post-grafting immunosuppression. The two BMT patients with GF were successfully rescued with a PBSC second transplant. In the two cases where a PBSCT was done as a first option no GF was observed and a successful and complete haematological recovery was achieved. In conclusion, PBSCT rescued two SAA patients with GF after BMT. PBSCT without ATG as a first option produced a quick and complete haematological recovery in two additional patients, suggesting that PBSCT without ATG can be an alternative to BMT plus ATG in SAA as a first transplant option.     

Bone marrow transplantation from identical twins in the treatment of aplastic anaemia: implication for the pathogenesis of the disease

S ummary . Treatment of aplastic anaemia by bone marrow transplantation from a syngeneic (identical twin) donor has provided insights into the pathophysiology of the disease.
We report from patients with severe anaemia who were treated by syngeneic bone marrow transplantation. None of the patients had sustained recovery of peripheral blood counts. All four received second transplants from the same twin donor after immunosuppressive conditioning treatment. Each had prompt recovery of haematopoiesis. A review of the literature indicates that failure of syngeneic bone marrow transplantation in patients with aplastic anaemia is not uncommon. These data indicate that aplastic anaemia may be caused by a mechanism other than an absence or intrinsic abnormality of haematopoietic stem cells in many patients.     

Unrelated donor bone marrow transplantation for children and adolescents with aplastic anaemia or myelodysplasia

Allogeneic transplantation from an HLA-matched family member has been shown to be effective in reconstituting normal haemopoiesis in young people with severe cytopenias, classified as myelodysplastic syndrome (MDS) or severe aplastic anaemia (SAA). Unrelated donor transplant is a therapeutic choice for patients without a suitable family member donor. We report the outcome of seven patients < 20 years old with SAA and 10 with MDS treated with BMT from an HLA A,B DRB1 matched ( n  =8) or A or B locus mismatched ( n  =9) unrelated donor at the University of Minnesota between March 1988 and August 1995. Primary graft failure occurred in two patients and secondary graft failure in one, who was subsequently successfully engrafted with a second donor marrow infusion. Grades II–IV GVHD occurred in 10/16 (63%), and grades III–IV in 6/16 (37%) evaluable patients. Nine of the 17 patients (six with MDS and three with SAA) survive with full donor chimaerism, a median of 1.2 years post-BMT (range 3 months to 7 years). We recommend early referral for consideration of unrelated donor BMT for young patients with MDS, and patients with SAA without response to immunosuppression.     

Single institution outcomes of treatment of severe aplastic anaemia

Background: In severe aplastic anaemia, the treatment of choice for young patients with a human leucocyte antigen‐matched sibling is now established as allogeneic bone marrow transplantation (BMT). In older patients and in those without a matched sibling donor, immunosuppressive therapy is the usual first option. ‘Alternative’ marrow donors are emerging as an option for those without a matched sibling donor. Aims: To review 10 years of local experience in treating severe aplastic anaemia with BMT and immunosuppressive therapy with emphasis on long‐term outcomes. Methods: A retrospective analysis was performed of all patients with severe aplastic anaemia presenting to the Royal Brisbane and Royal Children’s Hos‐ pitals between 1989 and 1999. Data were abstracted regarding patient demographics, pretreatment characteristics and outcome measures, including response rates, overall survival and long‐term complications. Results: Twenty‐seven consecutive patients were identified, 12 treated with immunosuppression alone and 15 with BMT. In these two groups, transfusion independence was attained in 25% and 100%, respectively, with overall survival being 36% and 100%, respectively. Those treated with immunosuppression were significantly older (median 41.5 versus 22 years, P = 0.008). Long‐term survivors of either treatment had extremely low morbidity. Three patients carried pregnancies to term post‐transplant. Three patients received alternative donor BMT with correspondingly excellent survival. Conclusions: Patients treated with allogeneic BMT for severe aplastic anaemia enjoyed extremely good long‐term survival and minimal morbidity. Patients treated with immunosuppressive therapy had a poorer outcome reflecting their older age and different usage of therapies over the past decade. Optimal treatment strategies for severe aplastic anaemia remain to be determined. (Intern Med J 2001; 31: 337–342)     

An update on the management of severe idiopathic aplastic anaemia in children

The current outlook for a child with severe idiopathic aplastic anaemia (AA) is very much better than in previous decades. In part, this may reflect better differentiation of idiopathic and inherited marrow failure. For children with idiopathic AA and a human leucocyte antigen (HLA)-matched sibling donor (MSD), allogeneic haematopoietic stem-cell transplantation (AHSCT) is the primary therapy of choice, offering long-term disease-free survival of 90%, although graft-versus-host disease remains a cause of long-term morbidity. A greater treatment challenge remains for those children without a MSD. Combination immunosuppressive therapy (IST) is associated with response rates of 70% or more. However, relapse and clonal evolution with transformation to myelodysplasia or acute myeloid leukaemia remain significant problems after IST and long-term event-free survival rates are less impressive. For children who do not have a sustained response to IST, alternate donor AHSCT should be considered. New HLA typing technologies, novel stem cell sources, reduced-intensity conditioning and graft engineering have reduced toxicity and improved the outcome after alternate donor AHSCT. Emerging therapies that capitalise on recent advances in our understanding of the pathophysiology of idiopathic AA and the immunobiology of AHSCT and IST may further improve the long-term outcome of this disease.     

Similar outcome of upfront‐unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party,Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT

We explored the feasibility of unrelated donor haematopoietic stem cell transplant (HSCT) upfront without prior immunosuppressive therapy (IST) in paediatric idiopathic severe aplastic anaemia (SAA). This cohort was then compared to matched historical controls who had undergone first‐line therapy with a matched sibling/family donor (MSD) HSCT (n = 87) or IST with horse antithymocyte globulin and ciclosporin (n = 58) or second‐line therapy with unrelated donor HSCT post‐failed IST (n = 24). The 2‐year overall survival in the upfront cohort was 96 ± 4% compared to 91 ± 3% in the MSD controls (P = 0·30) and 94 ± 3% in the IST controls (P = 0·68) and 74 ± 9% in the unrelated donor HSCT post‐IST failure controls (P = 0·02).The 2‐year event‐free survival in the upfront cohort was 92 ± 5% compared to 87 ± 4% in MSD controls (P = 0·37), 40 ± 7% in IST controls (P = 0·0001) and 74 ± 9% in the unrelated donor HSCT post‐IST failure controls (n = 24) (P = 0·02). Outcomes for upfront‐unrelated donor HSCT in paediatric idiopathic SAA were similar to MSD HSCT and superior to IST and unrelated donor HSCT post‐IST failure. Front‐line therapy with matched unrelated donor HSCT is a novel treatment approach and could be considered as first‐line therapy in selected paediatric patients who lack a MSD.     

Treatment of aplastic anemia with a monoclonal antibody directed against the interleukin-2 receptor

Summary Severe aplastic anemia (SAA) has been related in most cases to underlying autoimmune conditions. Various immunosuppressive regimens have been recommended in the absence of an HLA-identical bone marrow donor. Prednisolone, antithymocyte globulin, and cyclosporin A have been shown to be effective. This report describes the successful treatment of a 23-year-old woman suffering from severe aplastic anemia who had become multiresistant against previously administered immunosuppressive agents, using a monoclonal IL-2-receptor blocking antibody. The patient responded within 4 weeks. The time to the next relapse was 8 months; however, another remission with a second course of horse-antithymocyte globulin was achieved and has been maintained for 27 months to date with low doses of cyclosporin A. Although this is an anecdotical report, IL-2-receptor blockade using a monoclonal antibody might be considered as a further alternative in multiresistant SAA, perhaps increasing the susceptibility to further immunosuppressive trials.     

Matched sibling donors versus alternative donors in allogeneic hematopoietic stem cell transplantation for pediatric severe aplastic anemia in México

Abstract

Objectives

Hematopoietic stem cell transplantation (HSCT) from a matched sibling donor (MSD) is the preferred initial treatment for children with severe aplastic anemia (SAA). Unfortunately, only about 30% of patients have a suitable human leukocyte antigen-matched sibling.

Methods

We have analyzed the outcome of 42 patients who received HSCT (22 MSD and 20 alternative donors (AD)) for SAA at the seven major pediatric HSCT centers in Mexico between 2001 and 2013.

Results

With a median follow-up of 30 months (range, 0.4–144), the 5-year overall survival in children transplanted from MSD was 86.4 + 7.3 vs. 49.5 + 11% for children after AD-HSCT (P = 0.013). The cumulative incidence of treatment-related mortality (TRM) was in the MSD-HSCT 9.1 + 3.9% vs. 47.6 + 9.1% in the AD-HSCT context (P = 0.007). Infectious complications contributed to death (91%) of most patients who received AD-HSCT.

Discussion

Even when the results of patients given MSD-HSCT are adequate, there is still much room for improvement particularly in children allografted with AD and in the supportive care. The development of an economicwise designed prospective project with MSD or matched unrelated donor HSCTs as a first line of treatment of children with SAA as a unified national trial could address these issues.     

Recombinant human erythropoietin is effective in correcting erythropoietin-deficient anaemia after allogeneic bone marrow transplantation.

Two children affected by severe aplastic anaemia (SAA) underwent allogeneic bone marrow transplantation (BMT) using partially matched family donors. In both cases there was a successful engraftment of donor haemopoietic stem cells. However, after an initial erythropoietic recovery, 5 months following BMT both children became severely anaemic. Although multiple factors were responsible for anaemia, in both cases there was a markedly impaired erythropoietin response to anaemia, as indicated by the inappropriately low levels of serum erythropoietin (EPO). Treatment with recombinant human erythropoietin (rHuEPO) induced a sustained erythropoietic response with complete correction of anaemia. This pilot study suggests that rHuEPO can be effective in correcting long-lasting anaemia after marrow transplantation, characterized by inadequate erythropoietin production.     

Results of immunosuppression in aplastic anaemia

The availability of immunosuppressive agents, such as antilymphocyte globulin and cyclosporin, has had a major impact on the outcome of patients with aplastic anaemia. The majority of patients will show a response to immunosuppressive therapy. For those who fail to respond to an initial course, a second or further courses of immunosuppression can be given. Improvement in survival may also be due to the improved quality of supportive care available today for patients with aplastic anaemia. The additional use of haemopoietic growth factors such as granulocyte colony stimulating factor with immunosuppressive therapy requires further prospective randomised studies in order to evaluate whether they are of benefit for patients with aplastic anaemia. Because of the rarity of this condition, the use of multicentre prospective randomised studies is crucial for further evaluation of treatment modalities in aplastic anaemia.     

Oral cyclosporin-A is effective treatment for untreated and also for previously immunosuppressed patients with severe bone marrow failure

16 patients with transfusion-dependent, life-threatening bone marrow failure (14 with severe aplastic anaemia, 1 with systemic lupus erythematosus and 1 with pure red cell aplasia) were treated with cyclosporin-A (Cy-A) after either lack of response to conventional immunosuppression with antithymocyte-globulin/high-dose methylprednisolone for 95 to 1190 days (median 186.5) (group I, 8 patients) or as a primary treatment due to ineligibility for conventional immunosuppression (group II, 8 pat.). Cyclosporin-A was given orally to maintain trough levels of 200 to 300 ng/ml (RIA). In group I, 6 out of 8 patients responded 30 to 480 d (median 53) and are currently alive 627 to 1482 d (median 731) after initiation of Cy-A, respectively. In 3 of the responders Cy-A has been withdrawn, without relapse. In group II, 5 of 8 patients responded 26 to 170 d (median 63) and are currently alive 142 to 697 (median 420) d following initiation of Cy-A, respectively. These data indicate a place for cyclosporin-A in the management of patients with life-threatening bone marrow failure in whom a) immunosuppressive therapy with antithymocyte-globulin and high-dose methylprednisolone had failed and b) who are not candidates for vigorous immunosuppression or bone marrow transplantation, for medical or other reasons.     

Reduced-intensity conditioning and blood stem cell transplantation from an HLA-identical sibling for severe aplastic anaemia: two patients with successful engraftment but a fatal post-transplant lymphoproliferative disorder in the other

Allogeneic stem cell transplantation with reduced-intensity conditioning (RIC) can be offered to patients who are ineligible for high-dose conditioning because of their age or comorbidities. Malignant haematological diseases have so far been the most common indication of this new treatment modality; it has been less often used for nonmalignant diseases, and there are only a few reports of RIC and allotransplantation to treat acquired severe aplastic anaemia (SAA). We report two elderly patients (62 and 65 years of age) with SAA who underwent RIC (fludarabine + cyclophosphamide + ATG) and HLA-identical sibling allogeneic blood stem cell transplantation. Two important findings emerged. First, both of our patients who had failed standard immunological treatments and had a heavy transfusion history experienced successful engraftment after RIC and blood allografting, and one of them continues in full haematological remission 20+ months post-transplant. Secondly, the other patient died of Epstein-Barr virus-associated post-transplant lymphoproliferative disorder (PTLD) soon after engraftment, which implies that even if PTLD has been described in only few single cases after RIC, it may also complicate RIC allotransplants.