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Purpose: Secondary myeloid neoplasms (sMNs) remain the most serious long-term complications in patients with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). However, sMNs lack specific predictors, dedicated surveillance measures, and early therapeutic interventions., Patients and Methods: We studied a multicenter, retrospective cohort of 1,008 patients (median follow-up 8.6 years) with AA and PNH to assess clinical and molecular determinants of clonal evolution., Results: Although none of the patients transplanted upfront (n = 117) developed clonal complications (either sMN or secondary PNH), the 10-year cumulative incidence of sMN in nontransplanted cases was 11.6%. In severe AA, older age at presentation and lack of response to immunosuppressive therapy were independently associated with increased risk of sMN, whereas untreated patients had the highest risk among nonsevere cases. The elapsed time from AA to sMN was 4.5 years. sMN developed in 94 patients. The 5-year overall survival reached 40% and was independently associated with bone marrow blasts at sMN onset. Myelodysplastic syndrome with high-risk phenotypes, del7/7q, and ASXL1 , SETBP1 , RUNX1 , and RAS pathway gene mutations were the most frequent characteristics. Cross-sectional studies of clonal dynamics from baseline to evolution revealed that PIGA/ human leukocyte antigen lesions decreased over time, being replaced by clones with myeloid hits. PIGA and BCOR/L1 mutation carriers had a lower risk of sMN progression, whereas myeloid driver lesions marked the group with a higher risk., Conclusion: The risk of sMN in AA is associated with disease severity, lack of response to treatment, and patients' age. sMNs display high-risk morphological, karyotypic, and molecular features. The landscape of acquired somatic mutations is complex and incompletely understood and should be considered with caution in medical management.

Background: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia., Methods: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months., Results: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome., Conclusions: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.)., (Copyright © 2022 Massachusetts Medical Society.)

In the absence of an HLA-matched donor, the best treatment for acquired aplastic anemia patients refractory to immunosuppression is unclear. We collected and analyzed data from all acquired aplastic anemia patients who underwent a haploidentical transplantation with posttransplant cyclophosphamide in Europe from 2011 to 2017 (n = 33). The cumulative incidence of neutrophil engraftment was 67% (CI 95% : 51-83%) at D +28 and was unaffected by age group, stem cell source, ATG use, or Baltimore conditioning regimen. The cumulative incidence of grades II-III acute GvHD was 23% at D +100, and limited chronic GvHD was 10% (0-20) at 2 years, without cases of grade IV acute or extensive chronic GvHD. Two-year overall survival was 78% (64-93), and 2-year graft-versus-host disease-free survival was 63% (46-81). In univariate analysis, the 2-year OS was higher among patients who received the Baltimore conditioning regimen (93% (81-100) versus 64% (41-87), p = 0.03), whereas age group, stem cell source, and ATG use had no effect. Our results using unmanipulated haploidentical transplantation and posttransplant cyclophosphamide for treating refractory AA patients are encouraging, but warrant confirmation in a prospective study with a larger number of patients and longer follow-up.

This follow-up study of a randomized, prospective trial included 192 patients with newly diagnosed severe aplastic anemia receiving antithymoglobulin and cyclosporine, with or without granulocyte colony-stimulating factor (G-CSF). We aimed to evaluate the long-term effect of G-CSF on overall survival, event-free survival, probability of secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), clinical paroxysmal nocturnal hemoglobinuria, relapse, avascular osteonecrosis and chronic kidney disease. The median follow-up was 11.7 years (95% CI, 10.9-12.5). The overall survival rate at 15 years was 57±12% in the group given G-CSF and 63±12% in the group not given G-CSF ( P =0.92); the corresponding event-free survival rates were 24±10% and 23±10%, respectively ( P =0.36). In total, 9 patients developed MDS or AML, 10 only a clonal cytogenetic abnormality, 7 a solid cancer, 18 clinical paroxysmal nocturnal hemoglobinuria, 8 osteonecrosis, and 12 chronic kidney disease, without any difference between patients treated with or without G-CSF. The cumulative incidence of MDS, AML or isolated cytogenetic abnormality at 15 years was 8.5±3% for the G-CSF group and 8.2±3% for the non-G-CSF group ( P =0.90). The cumulative incidence of any late event including myelodysplastic syndrome or acute myeloid leukemia, isolated cytogenetic abnormalities, solid cancer, clinical paroxysmal nocturnal hemoglobinuria, aseptic osteonecrosis, chronic kidney disease and relapse was 50±12% for the G-CSF group and 49±12% for the non-G-CSF group ( P =0.65). Our results demonstrate that it is unlikely that G-CSF has an impact on the outcome of severe aplastic anemia; nevertheless, very late events are common and eventually affect the prognosis of these patients, irrespectively of their age at the time of immunosuppressive therapy (NCT01163942)., (Copyright© 2020 Ferrata Storti Foundation.)

Aplastic anemia is a rare but potentially life-threatening disease that may affect older patients. Data regarding the treatment of aplastic anemia in this ageing population remains scarce. We conducted a retrospective nationwide multicenter study in France to examine current treatments for aplastic anemia patients over 60 years old. Our aims were to evaluate efficacy and tolerance, and to analyze predictive factors for response and survival. Over the course of a decade, 88 patients (median age 68.5 years) were identified in 19 centers, with a median follow up of 2.7 years; 21% had very severe and 36% severe aplastic anemia. We analyzed 184 treatment lines, mostly involving the standard combination of anti-thymocyte globulin and cyclosporine-A (33%), which was also the most frequent first-line treatment (50%). After first-line therapy, 32% of patients achieved a complete response, and 15% a partial response. Responses were significantly better in first line and in patients with good performance status, as well as in those that had followed an anti-thymocyte globulin and cyclosporine-A regimen (overall response rate of 70% after first-line treatment). All treatments were well tolerated by patients, including over the age of 70. Three-year survival was 74.7% (median 7.36 years). Age, Charlson comorbidity index and very severe aplastic anemia were independently associated with mortality. Age, per se, is not a limiting factor to aplastic anemia treatment with anti-thymocyte globulin and cyclosporine-A; this regimen should be used as a first-line treatment in elderly patients if they have a good performance status and low comorbidity index score., (Copyright © 2019 Ferrata Storti Foundation.)

We retrospectively analyzed the outcomes of 1837 adults and children with severe aplastic anemia (SAA) who underwent matched sibling donor (MSD) and matched unrelated donor (MUD) hemopoietic stem cell transplantation (HSCT) between 2000 and 2013. Patients were grouped by transplant conditioning containing either anti-thymocyte globulin (ATG) (n = 1283), alemtuzumab (n = 261), or no serotherapy (NS) (n = 293). The risks of chronic GvHD were significantly reduced when ATG or alemtuzumab were compared with NS (P = .021 and .003, respectively). Acute GVHD was significantly reduced in favor of alemtuzumab compared with ATG (P = .012) and NS (P < .001). By multivariate analysis, when compared with ATG, alemtuzumab was associated with a lower risk of developing acute (OR 0.262; 95% CI 0.14-0.47; P < .001) and chronic GVHD (HR 0.58; 95% CI 0.35-0.94; P = .027). OS was significantly better in ATG and alemtuzumab patients compared with NS (P = .010 and .025). Our data shows inclusion of serotherapy in MSD and MUD HSCT for patients with SAA reduces chronic GVHD and provides a survival advantage over patients not receiving serotherapy. Notably, alemtuzumab reduced the risk of acute and chronic GvHD compared with ATG and indicates that alemtuzumab might be the serotherapy of choice for MSD and MUD transplants for SAA., (© 2018 Wiley Periodicals, Inc.)

The incidence of acquired aplastic anaemia (AA) peaks in adolescents and young adults (AYA). Although age has been associated with response after immunosuppressive therapy (IST), few data exist about the specific outcome of AYA. We retrospectively compared the outcome of 29 children (aged <15 years), 32 AYA (15-25 years) and 23 adults (>25 years) with AA treated front-line with IST in Saint-Louis Hospital. The cumulative incidence of response was lower in adults compared with AYA (subdistribution hazard ratio [SHR] = 0·38, 95% confidence interval [CI] [0·96-1·00], P = 0·008), but no difference was observed between children and AYA (SHR = 0·84, 95% CI [0·96-1·00], P = 0·56), with a 6 months cumulative incidence of partial response of 44·8% in children, 62·5% in AYA and 21·7% in adults. The 5-year failure-free survival was 48·4%, without impact of age, with a 5-year relapse rate of 20·7%. With a median follow-up of 5·4 years, the 5-year overall survival was 86·5%, without significant difference between children and AYA overall survival (hazard ratio [HR] 1·51, 95% CI [0·25-9·02], P = 0·66), while adults displayed poorer survival than AYA (HR 4·98, 95% CI [1·00-24·73], P = 0·049). This study confirms that age is a prognostic factor in AA patients treated with IST. However, AYA patients have a similar outcome to children in terms of response rate and survival., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Outcomes remain poor for refractory severe aplastic anemia (SAA) patients. Alternative donor transplantation may be considered, but results from previous studies are not encouraging. We conducted a prospective nationwide phase 2 study to assess unrelated cord blood (CB) transplantation (CBT) efficacy and safety in refractory SAA patients (Aplastic Anemia and Cord Blood Transplantation protocol). To demonstrate a significant difference in 1-year survival from 20% (null hypothesis) to 50% (alternative hypothesis), we needed to include 25 transplanted patients and therefore included 26 (median age, 16 years). Eligibility criteria required 1 or 2 unrelated CB units, containing separately or together >4 × 10 7 frozen nucleated cells (NCs) per kilogram of recipient body weight. Conditioning regimen comprised fludarabine (FLU), cyclophosphamide (CY), antithymocyte globulin (ATG), and 2-Gy total body irradiation (TBI). With a median follow-up of 38.8 months, engraftment occurred in 23 patients (88%); cumulative incidences of grade II-IV acute and chronic graft-versus-host disease were 45.8% and 36%, respectively. Twenty-three patients were alive at 1 year, with an 88.5% overall survival (OS) rate, differing significantly from the expected 20% ( P < .0001; 84% OS at 2 years). CBT with units containing ≥4 × 10 7 frozen NCs per kilogram is therefore a valuable curative option for young adults with refractory SAA and no available matched unrelated donors. This trial was registered at www.clinicaltrials.gov as #NCT01343953., (© 2018 by The American Society of Hematology.)

Antithymocyte globulins (ATG) plus cyclosporine (CSA) is the gold standard immunosuppressive treatment (IST) for patients with aplastic anemia. A prospective randomized trial showed in 2011 that hATG was superior to rabbit ATG for first-line treatment of severe AA. The French Health Agency (ANSM) permitted a patient-named authorization for temporary use (ATU) program of hATG (ATGAM, Pfizer) in patients with AA in 2011 since commercial access to hATG is not approved. We took advantage of this program to analyze the outcomes of 465 patients who received antithymocyte globulins (ATGAM) plus CSA as first line treatment (n = 379; 81.5%), or for refractory (n = 26) or relapsed disease (n = 33), from September 2011 to March 2017. In the entire cohort one year, 72% of the patients had partial and 13% had complete response, with worse response for patients with severe AA and a longer interval between diagnosis and IST (more than 6 months). Severe adverse events were mainly linked to infections (24%), hemorrhages (6%), and elevated liver function tests (5%). Overall at 12 months, 9.7% of patients required second line IST and 15.6% received transplantation. Fifty-five patients died during the study mainly because of infections (53%). Factors predicting independently worse survival were age over 40 years, neutrophils less than 0.5 × 10 9 /L, male gender and longer delay between diagnosis and hATG (>6 months period). This study does illustrate the results of ATGAM with CSA in a true-life perspective and confirms ATGAM as standard of care IST to treat patients with AA not eligible for HSCT., (© 2018 Wiley Periodicals, Inc.)

Few therapeutic options are available for patients with aplastic anemia who are ineligible for transplantation or refractory to immunosuppressive therapy. Eltrombopag was recently shown to produce trilineage responses in refractory patients. However, the effects of real-life use of this drug remain unknown. This retrospective study (2012-2016) was conducted by the French Reference Center for Aplastic Anemia on patients with relapsed/refractory aplastic anemia, and patients ineligible for antithymocyte globulin or transplantation, who received eltrombopag for at least 2 months. Forty-six patients with aplastic anemia were given eltrombopag without prior antithymocyte globulin treatment (n=11) or after antithymocyte globulin administration (n=35) in a relapsed/refractory setting. Eltrombopag (median daily dose 150 mg) was introduced 17 months (range, 8-50) after the diagnosis of aplastic anemia. At last followup, 49% were still receiving treatment, 9% had stopped due to a robust response, 2% due to toxicity and 40% due to eltrombopag failure. Before eltrombopag treatment, all patients received regular transfusions. The overall rates of red blood cell and platelet transfusion independence were 7%, 33%, 46% and 46% at 1, 3, 6 months and last follow-up. Responses were slower to develop in antithymocyte treatment-naïve patients. In patients achieving transfusion independence, hemoglobin concentration and platelet counts improved by 3 g/dL (interquartile range, 1.4-4.5) and 42×10 9 /L (interquartile range, 11-100), respectively. Response in at least one lineage (according to National Institutes of Health criteria) was observed in 64% of antithymocyte treatment-naïve and 74% of relapsed/refractory patients, while trilineage improvement was observed in 27% and 34%, respectively. We found high rates of hematologic improvement and transfusion independence in refractory aplastic anemia patients but also in patients ineligible for antithymocyte globulin receiving first-line treatment. In conclusion, elderly patients unfit for antithymocyte globulin therapy may benefit from eltrombopag., (Copyright© 2018 Ferrata Storti Foundation.)

We describe a new syndrome characterized by early-onset diabetes associated with bone marrow failure, affecting mostly the erythrocytic lineage. Using whole-exome sequencing in a remotely consanguineous patient from a family with two affected siblings, we identified a single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located in the dUTPase ( DUT ) gene (National Center for Biotechnology Information Gene ID 1854), affecting both the mitochondrial (DUT-M p.Y142C) and the nuclear (DUT-N p.Y54C) isoforms. We found the same homozygous mutation in an unrelated consanguineous patient with diabetes and bone marrow aplasia from a family with two affected siblings, whereas none of the >60,000 subjects from the Exome Aggregation Consortium (ExAC) was homozygous for this mutation. This replicated observation probability was highly significant, thus confirming the role of this DUT mutation in this syndrome. DUT is a key enzyme for maintaining DNA integrity by preventing misincorporation of uracil into DNA, which results in DNA toxicity and cell death. We showed that DUT silencing in human and rat pancreatic β-cells results in apoptosis via the intrinsic cell death pathway. Our findings support the importance of tight control of DNA metabolism for β-cell integrity and warrant close metabolic monitoring of patients treated by drugs affecting dUTP balance., (© 2017 by the American Diabetes Association.)

Background: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare disease. Although much progress has been made in the understanding of the pathophysiology of the disease, far less is known with respect to the clinical outcomes of patients with PNH. Few retrospective studies provide survival estimates, and even fewer have explored the clinical heterogeneity of the disease. Haemolytic and aplastic anaemia (AA) forms of the disease have been recognised as main disease categories, with the haemolytic form being associated with the worst prognosis by the largest studied cohort some years ago., Aims: To describe mortality and causes of death in PNH overall and by PNH classification and to evaluate risk factors associated with mortality., Methods: We analysed data of 2356 patients enrolled in the International PNH Registry with multivariate analyses, using time-dependent covariates. Patients were classified into haemolytic, AA/PNH syndrome or intermediate PNH., Results: Overall, 122 (5.2%) patients died after enrolment, the incidence according to subcategories being 5.1, 11.7, 2.0 and 4.8% for patients with haemolytic PNH, AA-PNH, intermediate and insufficient data respectively. Older age and decreased performance status also affected survival in multivariate analysis. Improved outcome of patients with haemolytic PNH suggests that eculizumab treatment in PNH may be associated with improved survival., Conclusion: A detailed analysis of clinical presentations and causes of death in patients with PNH, overall and by disease subcategories, provide evidence that in the current era, patients with haemolytic PNH are no longer those who harbour the worst prognosis. This finding differs sharply from what has been previously reported., (© 2016 Royal Australasian College of Physicians.)

Unrelated allogeneic transplantation for severe aplastic anemia is a treatment option after immunosuppressive treatment failure in the absence of a matched sibling donor. Age, delay between disease diagnosis and transplantation, and HLA matching are the key factors in transplantation decisions, but their combined impact on patient outcomes remains unclear. Using the French Society of Bone Marrow Transplantation and Cell Therapies registry, we analyzed all consecutive patients (n=139) who underwent a first allogeneic transplantation for idiopathic severe aplastic anemia from an unrelated donor between 2000 and 2012. In an adjusted multivariate model, age over 30 years (Hazard Ratio=2.39; P=0.011), time from diagnosis to transplantation over 12 months (Hazard Ratio=2.18; P=0.027) and the use of a 9/10 mismatched unrelated donor (Hazard Ratio=2.14; P=0.036) were independent risk factors that significantly worsened overall survival. Accordingly, we built a predictive score using these three parameters, considering patients at low (zero or one risk factors, n=94) or high (two or three risk factors, n=45) risk. High-risk patients had significantly shorter survival (Hazard Ratio=3.04; P<0.001). The score was then confirmed on an independent cohort from the European Group for Blood and Marrow Transplantation database of 296 patients, with shorter survival in patients with at least 2 risk factors (Hazard Ratio=2.13; P=0.005) In conclusion, a simple score using age, transplantation timing and HLA matching would appear useful to help physicians in the daily care of patients with severe aplastic anemia., (Copyright© Ferrata Storti Foundation.)

Combinations of cyclosporine (CSP) with methotrexate (MTX) have been widely used for immunosuppression after allogeneic transplantation for acquired aplastic anemia. We compared outcomes with tacrolimus (TAC)+MTX versus CSP+MTX after transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) in a retrospective cohort of 949 patients with severe aplastic anemia. Study endpoints included hematopoietic recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, and mortality. TAC+MTX was used more frequently in older patients and, in recent years, in both SIB and URD groups. In multivariate analysis, TAC+MTX was associated with a lower risk of mortality in URD recipients and with slightly earlier absolute neutrophil count recovery in SIB recipients. Other outcomes did not differ statistically between the 2 regimens. No firm conclusions were reached regarding the relative merits of TAC+MTX versus CSP+MTX after hematopoietic cell transplantation for acquired aplastic anemia. Prospective studies would be needed to determine whether the use of TAC+MTX is associated with lower risk of mortality in URD recipients with acquired aplastic anemia., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We have analyzed 1448 patients with acquired aplastic anemia grafted between 2005 and 2009, and compared outcome of identical sibling (n=940) versus unrelated donor (n=508) transplants. When compared to the latter, sibling transplants were less likely to be performed beyond 180 days from diagnosis (39% vs. 85%), to have a cytomegalovirus negative donor/recipient status (15% vs. 23%), to receive antithymocyte globulin in the conditioning (52% vs. 61%), and more frequently received marrow as a stem cell source (60% vs. 52%). Unrelated donor grafts had significantly more acute grade II-IV (25% vs. 13%) and significantly more chronic graft-versus-host disease (26% vs. 14%). In multivariate analysis, the risk of death of unrelated donor grafts was higher, but not significantly higher, compared to a sibling donor (P=0.16). The strongest negative predictor of survival was the use of peripheral blood as a stem cell source (P<0.00001), followed by an interval of diagnosis to transplant of 180 days or more (P=0.0005), patient age 20 years or over (P=0.0005), no antithymocyte globulin in the conditioning (P=0.003), and donor/recipient cytomegalovirus sero-status, other than negative/negative (P=0.04). In conclusion, in multivariate analysis, the outcome of unrelated donor transplants for acquired aplastic anemia, is currently not statistically inferior when compared to sibling transplants, although patients are at greater risk of acute and chronic graft-versus-host disease. The use of peripheral blood grafts remains the strongest negative predictor of survival., (Copyright© Ferrata Storti Foundation.)

We analyzed the outcome of 537 adolescents (age 12-18 years) with idiopathic aplastic anemia included in the database of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation comparing: i) matched family donor hematopoietic stem cell transplantation performed as first-line treatment with ii) front-line immunosuppressive therapy not followed by subsequent transplant given for failure and with iii) hematopoietic stem cell transplantation performed after failed front-line immunosuppressive therapy. Overall survival was 86% in the matched family donor hematopoietic stem cell transplantation group, 90% in patients given front-line immunosuppressive alone (those who did not fail this treatment and who did not receive subsequent rescue with hematopoietic stem cell transplantation) and 78% in subjects who underwent hematopoietic stem cell transplantation post failed front-line immunosuppressive therapy (P=0.14). Event-free survival in the same groups was respectively 83%, 64% and 71% (P=0.04). Cumulative incidence of rejection was 8% in matched family donor hematopoietic stem cell transplantation and 9% in transplants post failed front-line immunosuppression (P=0.62). Cumulative incidence of acute graft-versus-host disease was 12% in matched family donor transplants and 18% in transplants post failed immunosuppression (P=0.18). Chronic graft-versus-host disease was higher in matched family donor hematopoietic stem cell transplantation (8%) than in transplants post failed immunosuppressive therapy (20%) (P=0.0009). Cumulative incidence of post-therapy malignancies was 0.7% in matched family donor transplantations, 7% in transplantations post failed immunosuppression and 21% after front-line immunosuppression (P=0.0017). In the whole cohort, under multivariate analysis, the diagnosis to treatment interval of two months or under positively affected overall survival whereas up-front immunosuppression alone (with no subsequent rescue transplants) negatively affected event-free survival. In transplanted patients an interval from diagnosis to treatment of 2 months or under, bone marrow as source of cells and first-line matched family donor transplants provided a significant advantage in overall and event-free survival. Aplastic anemia in adolescents has a very good outcome. If a matched family donor is available, hematopoietic stem cell transplantation using bone marrow cells is the first choice treatment. If such a donor is not available, immunosuppressive treatment may still be an acceptable second choice, also because, in case of failure, hematopoietic stem cell transplantation is a very good rescue option., (Copyright© Ferrata Storti Foundation.)

One hundred and forty patients who had undergone hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) transformation after treatment of severe aplastic anemia (SAA) were identified in the European Group for Blood and Marrow Transplantation (EBMT) database. The median age at HSCT was 29 years (range, 1 to 66 years). The transplant donor was related in 49% cases and unrelated in 51% cases. The 5-year probability of relapse was 17%, and that of nonrelapse mortality was 41%. The 5-year overall survival was 45% ± 9%, better for patients untreated and patients in remission compared with patients with refractory disease. Our data indicate that allogeneic HSCT leads to prolonged survival in close to one-half of the patients transforming to MDS or AML from SAA., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Aplastic anemia is usually treated with immunosuppression or allogeneic transplant, depending on patient and disease characteristics. Syngeneic transplant offers a rare treatment opportunity with minimal transplant-related mortality, and offers an insight into disease mechanisms. We present here a retrospective analysis of all syngeneic transplants for aplastic anemia reported to the European Group for Blood and Marrow Transplantation. Between 1976 and 2009, 88 patients received 113 transplants. Most transplants (n=85) were preceded by a conditioning regimen, 22 of these including anti-thymocyte globulin. About half of transplants with data available (39 of 86) were followed by posttransplant immunosuppression. Graft source was bone marrow in the majority of cases (n=77). Transplant practice changed over time with more transplants with conditioning and anti-thymocyte globulin as well as peripheral blood stem cells performed in later years. Ten year overall survival was 93% with 5 transplant-related deaths. Graft failure occurred in 32% of transplants. Risk of graft failure was significantly increased in transplants without conditioning, and with bone marrow as graft source. Lack of posttransplant immunosuppression also showed a trend towards increased risk of graft failure, while anti-thymocyte globulin did not have an influence. In summary, syngeneic transplant is associated with a significant risk of graft failure when no conditioning is given, but has an excellent long-term outcome. Furthermore, our comparatively large series enables us to recommend the use of pre-transplant conditioning rather than not and possibly to prefer peripheral blood as a stem cell source.

Patients with severe aplastic anemia (SAA) without a sibling donor receive immunosuppressive treatment (IST) with anti-thymocyte globulin (ATG). In the case of no response to IST, a voluntary unrelated donor (VUD) search is usually started. This study analyzes the outcome of ATG-refractory SAA patients activating a VUD search. Of 179 patients, 68 had at least one HLA-A, -B, and -DR matched donor identified and underwent HSCT while 50 also with a donor were not transplanted because of early death (8), late response to IST (34), transplant refusal (1), or other (7). Conversely, 61 had no matched donor, 13 of those ultimately received a mismatched HSCT. All but one received marrow stem cells. Among patients aged <17 years, those with at least one matched donor had a significant higher 4-year survival as compared to others (79% ± 6% versus 53% ± 10%, P = 0.01). There was also a survival advantage independent of recipient age when the donor search was initiated in the recent 2000-2005 study-period (74% ± 6% versus 47% ± 10%, P < 0.05). In multivariate analysis, the identification of a matched VUD tended to impact favourably on survival in patients with a recent donor search (P = 0.07). This study provides evidence for the use of unrelated donor HSCT in children and adults with IST-refractory SAA., (Copyright © 2013 Wiley Periodicals, Inc.)

Diffuse eosinophilic fasciitis (Shulman disease) is a rare sclerodermiform syndrome that, in most cases, resolves spontaneously or after corticosteroid therapy. It has been associated with hematologic disorders, such as aplastic anemia. The clinical features and long-term outcomes of patients with eosinophilic fasciitis and associated aplastic anemia have been poorly described. We report the cases of 4 patients with eosinophilic fasciitis and associated severe aplastic anemia. For 3 of these patients, aplastic anemia was refractory to conventional immunosuppressive therapy with antithymocyte globulin and cyclosporine. One of the patients received rituximab as a second-line therapy with significant efficacy for both the skin and hematologic symptoms. To our knowledge, this report is the first to describe rituximab used to treat eosinophilic fasciitis with associated aplastic anemia. In a literature review, we identified 19 additional cases of eosinophilic fasciitis and aplastic anemia. Compared to patients with isolated eosinophilic fasciitis, patients with eosinophilic fasciitis and associated aplastic anemia were more likely to be men (70%) and older (mean age, 56 yr; range, 18-71 yr). Corticosteroid-containing regimens improved skin symptoms in 5 (42%) of 12 cases but were ineffective in the treatment of associated aplastic anemia in all but 1 case. Aplastic anemia was profound in 13 cases (57%) and was the cause of death in 8 cases (35%). Only 5 patients (22%) achieved long-term remission (allogeneic hematopoietic stem cell transplantation: n = 2; cyclosporine-containing regimen: n = 2; high-dose corticosteroid-based regimen: n = 1).

For patients with inherited BM failure (BMF) or those with acquired BMF who fail immunosuppressive therapy and who lack a suitable alternative donor, the prognosis remains poor. Umbilical cord blood transplantation has extended the availability of hematopoietic stem cell transplantation in the absence of a suitable donor. A recent EBMT study confirmed the feasibility of this treatment and highlighted the fundamental role of the TNC dose (>3.9 × 10(7)/kg TNC/kg) on both engraftment and OS using cord blood as stem cell source in severe aplastic anemia. However, this procedure is still experimental and should be evaluated only through prospective clinical trials.

Allogeneic BM transplantation from an HLA-identical sibling donor leads to long-term survival in the majority of patients (>80%). Therefore, survival is no longer the sole concern and attention has to be paid to decreasing the incidence and severity of long-term complications. For patients without a sibling donor, transplantation from a well-matched unrelated donor can be considered after failure of a previous course of immunosuppressive therapy. After transplantation from an HLA-identical sibling donor or from an unrelated one, the use of peripheral blood stem cells must be strongly discouraged because they have been systematically associated with an increased incidence of chronic GVHD compared with the use of BM as a stem cell source, leading to an unacceptably higher risk of treatment-related mortality in this setting. For as yet unknown reasons, the age limit after which transplantation results are less satisfactory remains 40 years of age.

Background: In the era of eculizumab, identifying patients with paroxysmal nocturnal hemoglobinuria who may benefit from allogeneic stem cell transplantation is challenging., Design and Methods: We describe the characteristics and overall survival of 211 patients transplanted for paroxysmal nocturnal hemoglobinuria in 83 EBMT centers from 1978 to 2007. Next, we conducted a comparison with a cohort of 402 non-transplanted patients with paroxysmal nocturnal hemoglobinuria diagnosed between 1950 and 2005 in 92 French centers. We compared the occurrence of complications (i.e. thromboembolism and aplastic anemia) using either an individual or a stratum-matching procedure., Results: After a median follow-up of 5 years, the 5-year overall survival rate ± standard error (%) was 68 ± 3 in the transplanted group (54 ± 7 in the case of thromboembolism, 69 ± 5 in the case of aplastic anemia without thromboembolism and 86 ± 6 in the case of recurrent hemolytic anemia without thromboembolism or aplastic anemia). Only thromboembolism as the indication for transplantation was associated with worse outcome (P=0.03). We identified 24 pairs of transplanted and non-transplanted patients with thromboembolism for the matched comparison, with worse overall survival for the transplanted patients (hazard ratio=10.0; 95% confidence interval, 1.3-78.1; P=0.007). This was confirmed by the global matching procedure (P=0.03). As regards aplastic anemia without thromboembolism, 30 pairs were identified for the matched comparison. It was not observed that transplanted patients had a significantly worse overall survival (hazard ratio=4.0; 95% confidence interval, 0.9-18.9; P=0.06). A global matching procedure was not feasible., Conclusions: Allogeneic stem cell transplantation is probably not a suitable treatment option for life-threatening thromboembolism in paroxysmal nocturnal hemoglobinuria.

Background: Bone marrow has been shown to be superior to peripheral blood, as a stem cell source, in young patients (<20 years of age) with acquired aplastic anemia undergoing a matched sibling transplant. The aim of this study was to test whether this currently also holds true for older patients with acquired aplastic anemia., Design and Methods: We analyzed 1886 patients with acquired aplastic anemia who received a first transplant from a human leukocyte antigen identical sibling between 1999 and 2009, with either bone marrow (n=1163) or peripheral blood (n=723) as the source of stem cells., Results: In multivariate Cox analysis negative predictors for survival were: patient's age over 20 years (RR 2.0, P<0.0001), an interval between diagnosis and transplantation of more than 114 days (RR 1.3, P=0.006), no anti-thymocyte globulin in the conditioning (RR 1.6, P=0.0001), a conditioning regimen other than cyclophosphamide (RR=1.3, P=0.008) and the use of peripheral blood as the source of stem cells (RR 1.6, P<0.00001). The survival advantage for recipients of bone marrow rather than peripheral blood was statistically significant in patients aged 1-19 years (90% versus 76% P<0.00001) as well as in patients aged over 20 years (74% versus 64%, P=0.001). The advantage for recipients of bone marrow over peripheral blood was maintained above the age of 50 years (69% versus 39%, P=0.01). Acute and chronic graft-versus-host disease were more frequent in peripheral blood transplants. Major causes of death were graft-versus-host disease (2% versus 6% in bone marrow and peripheral blood recipients, respectively), infections (6% versus 13%), and graft rejection (1.5% versus 2.5%)., Conclusions: This study shows that bone marrow should be the preferred stem cell source for matched sibling transplants in acquired aplastic anemia, in patients of all age groups.

We evaluated the role of granulocyte colony-stimulating factor (G-CSF) in patients with severe aplastic anemia (SAA) treated with antithymocyte globulin (ATG) and cyclosporine (CSA). Between January 2002 and July 2008, 192 patients with newly diagnosed SAA not eligible for transplantation were entered into this multicenter, randomized study to receive ATG/CSA with or without G-CSF. Overall survival (OS) at 6 years was 76% ± 4%, and event-free survival (EFS) was 42% ± 4%. No difference in OS/EFS was seen between patients randomly assigned to receive or not to receive G-CSF, neither for the entire cohort nor in subgroups stratified by age and disease severity. Patients treated with G-CSF had fewer infectious episodes (24%) and hospitalization days (82%) compared with patients without G-CSF (36%; P = .006; 87%; P = .0003). In a post hoc analysis of patients receiving G-CSF, the lack of a neutrophil response by day 30 was associated with significantly lower response rate (56% vs 81%; P = .048) and survival (65% vs 87%; P = .031). G-CSF added to standard ATG and CSA reduces the rate of early infectious episodes and days of hospitalization in very SAA patients and might allow early identification of nonresponders but has no effect on OS, EFS, remission, relapse rates, and mortality. This study was registered at www.clinicaltrials.gov as NCT01163942.

Information is scarce on outcomes after unrelated cord blood transplantation (UCBT) for patients with severe aplastic anemia (SAA). We retrospectively analyzed 71 patients (median age, 13 years; 28 adults) with SAA (9 with paroxysmal nocturnal hemoglobinuria [PNH]) who received a single-unit (n = 57; 79%) or double-unit UCBT (n = 14; 19%) in 32 centers between 1996 and 2009. A reduced-intensity conditioning regimen was provided in 68% of the patients. The cumulative incidence (CI) of neutrophil recovery was 51% ± 6% at day 60, with significantly better engraftment seen in recipients of higher prefreezing total nucleated cell (TNC) dose (>3.9 10(7)/kg; hazard ratio [HR], 1.5; P = .05). The CI of platelet engraftment at day 180 posttransplantation was 37% ± 7%, that of grade II-IV acute GVHD was 20% ± 5%, and that of chronic GVHD at 3 years was 18% ± 5%. At a median follow-up of 35 months (range, 3-83 months), the estimated probability of 3-year overall survival (OS) was 38% ± 6%. Significantly improved OS was seen in recipients of >3.9 10(7) TNCs/kg prefreezing (45%, compared with 18% for recipients of ≤ 3.9 10(7) TNC/kg; HR, 0.4; P = .007). These results highlight the fundamental role of cell dose for both engraftment and OS in patients with SAA undergoing UCBT., (2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Transplantation from an HLA-matched sibling is the treatment of choice for young patients with acquired severe aplastic anemia. For older patients, the acceptable upper age limit for transplantation as first-line treatment varies. The current analysis, therefore, sought to identify age or ages at transplantation at which survival differed., Design and Methods: We studied the effect of patients' age, adjusting for other significant factors affecting outcomes, in 1307 patients with severe aplastic anemia after HLA-matched sibling transplantation using logistic and Cox regression analysis. Age categories (<20 years, 20-40 years, >40 years) were determined using Martingale residual plots for overall survival and categories based on differences in survival., Results: Patients aged over 40 years old were more likely to have had immunosuppressive therapy, a poor performance score and a longer interval between diagnosis and transplantation. Neutrophil recovery was similar in all age groups but patients aged over 40 years had a lower likelihood of platelet recovery compared to patients aged less than 20 years (OR 0.45, P=0.01) but not compared to those aged 20-40 years (OR 0.60, P=0.10). Compared to the risk of mortality in patients aged less than 20 years, mortality risks were higher in patients over 40 years old (RR 2.70, P<0.0001) and in those aged 20-40 years (RR 1.69, P<0.0001). The mortality risk was also higher in patients aged over 40 years than in those 20-40 years old (RR 1.60, P=0.008)., Conclusions: Mortality risks increased with age. Risks were also higher in patients with a poor performance score and when the interval between diagnosis and transplantation was longer than 3 months, implying earlier referral would be appropriate when this treatment option is being considered.

Graft rejection, with persistent pancytopenia, is well documented after allogeneic BMT (hematopoietic SCT (HSCT)) for severe aplastic anemia (SAA) and the prognosis is poor. The recovery of host-hematopoiesis, autologous recovery (AR), after allogeneic HSCT is a rare event and the incidence and long-term survival are unknown. We report a retrospective analysis of consecutive patients in the Aplastic Anaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT-WPSAA) registry between 1973 and 2005. A total of 45 cases of AR, of 1205 patients transplanted for SAA in 57 centers are reported. We describe characteristics and long-term outcome of patients with AR, compared with SAA patients from participating transplant centers without AR (n=1024) and patients with graft rejection (n=136) without autologous recovery. The estimated cumulative incidence of AR was 4.2% (3.1-5.6) (confidence interval (CI) 95%) with an OS of 84% (95% CI 83-107%). The OS of the control group was 74% (81-90) at 10 years of follow up, whereas the patients with graft failure had an OS of 16% (CI 12-28%). This retrospective analysis establishes the incidence and long-term survival of patients experiencing AR after allogeneic HSCT for SAA.

In order to assess the epidemiology of Hepatitis-Associated Aplasia (HAA) and compare treatment outcome of HAA with non-HAA patients, we evaluated 3916 aplastic anaemia patients reported to the European Registry between 1990 and 2007. Year, month, season of diagnosis, type and outcome of first-line therapy were analysed. Prevalence of HAA (n = 214) in Europe was 5%. Compared to non-HAA patients, HAA patients were younger (15 vs. 20 years, P < 0.001), with a male prevalence (68% vs. 58% P = 0.002), and were treated earlier after diagnosis (46 vs. 62 d; P < 0.001). No significant differences were found regarding the year or month of diagnosis. No geographic clusters could be identified. Actuarial survival at 10 years after first-line immunosuppression was 69%, and did not differ according to aetiology. The 10-year actuarial survival after transplantation was 70%, and was comparable in HAA and non-HAA patients, when stratified for age and donor type. In a multivariate Cox analysis, increasing age and delayed treatment were significant negative indicators for survival. In conclusion, the incidence of HAA was 5% and was evenly distributed over time and geographic areas in Europe. Treatment outcome and predictive variables, were comparable in patients with or without HAA.

Older age is a limitation for HLA-identical sibling hematopoietic stem cell transplantation (HSCT) as first-line therapy for severe acquired idiopathic aplastic anemia (SAA). Fludarabine (Flu)-based conditioning might improve outcome in older patients. We analyzed retrospectively 30 patients older than 30 years receiving such reduced-intensity conditioning HSCT according to recommendations of the European Group for Blood and Marrow Transplantation (EBMT) and compared their outcome to a control group receiving the standard regimen (cyclophosphamide+/-antithymocyte globulin) over the same study period (1998-2007). Patients conditioned with Flu had a higher probability of overall survival than the control group (p=0.04) when adjusting for recipient's age. This might be related to a trend towards a reduced incidence of graft failure in patients receiving Flu (0% vs. 11%, p=0.09), while no difference was observed regarding graft-versus-host disease incidence. Flu-based conditioning regimen may reduce the negative impact of age in older patients with SAA receiving an HLA-identical sibling HSCT.

Ninety-one patients were studied serially for chimeric status following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA) or Fanconi Anaemia (FA). Short tandem repeat polymerase chain reaction (STR-PCR) was used to stratify patients into five groups: (A) complete donor chimeras (n = 39), (B) transient mixed chimeras (n = 15) (C) stable mixed chimeras (n = 18), (D) progressive mixed chimeras (n = 14) (E) recipient chimeras with early graft rejection (n = 5). As serial sampling was not possible in Group E, serial chimerism results for 86 patients were available for analysis. The following factors were analysed for association with chimeric status: age, sex match, donor type, aetiology of aplasia, source of stem cells, number of cells engrafted, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, occurrence of acute and chronic GvHD and survival. Progressive mixed chimeras (PMCs) were at high risk of late graft rejection (n = 10, P < 0.0001). Seven of these patients lost their graft during withdrawal of immunosuppressive therapy. STR-PCR indicated an inverse correlation between detection of recipient cells post-SCT and occurrence of acute GvHD (P = 0.008). PMC was a bad prognostic indicator of survival (P = 0.003). Monitoring of chimeric status during cyclosporin withdrawal may facilitate therapeutic intervention to prevent late graft rejection in patients transplanted for SAA.

The aim was to determine whether outcome of unrelated donor transplantation for severe aplastic anemia has improved in recent years and whether this is due to patient selection or better transplant technology. We analyzed 498 patients transplanted during 1990-2005. By running univariate regression models dichotomizing year of transplantation we defined 1998 as the year of the most significant change in survival. Five-year survival increased from 32+/-8% before 1998 to 57+/-8% after 1998 (P<0.0001). When comparing the cohort before (n=149) and after 1998 (n=349), there were no differences except for older age, and more frequent use of PBSCs, after 1998. High-resolution HLA typing data were unavailable. After 1998, there was less graft failure (11 vs 26%, P<0.0001), less acute GvHD (cumulative incidence 28 vs 37%, P=0.02) and less chronic GvHD (22 vs 38%, P=0.004). In multivariate analyses adjusting for differences in age, HLA-mismatch, performance score and time to transplantation, there was no change in the year of transplant effect (relative risk of death in transplants after 1998: 0.44 (95% confidence interval 0.33-0.59)). There is no evidence for patient selection to explain significantly improved survival in patients transplanted after 1998. We speculate that this is due to better donor matching.

Background and Objectives: Severe acquired aplastic anemia (SAA) is a potentially fatal bone marrow failure syndrome occurring mainly in children and young adults. Immunosuppressive regimens and hematopoietic stem cell transplantation (HSCT) are the only two available curative treatments. Patients who lack an HLA-identical sibling donor may receive HSCT from an unrelated donor, a strategy historically associated with high mortality rates. Thus, for patients refractory to immunosuppressive regimens, the decision to transplant stem cells from unrelated donors is weighed against supportive care and often represents a dilemma for physicians. We aimed to determine whether outcome after unrelated HSCT has improved in recent years and, if so, to determine the factors responsible for the improvement., Design and Methods: We analyzed the outcome of 89 patients (median age 17 years, range 0-52) with acquired SAA undergoing HSCT from an unrelated donor between 1989 and 2004. Cases were consecutively reported to the French Registry (SFGM-TC) by 25 centers., Results: Patients transplanted during two successive time-periods (1989-1998 and 1999-2004) had different 5-year survival probabilities (+/-95% confidence interval): 29%+/-7% and 50%+/-7%, respectively (p<0.01). The main difference between the two cohorts concerned HLA matching between donors and recipients at the allelic level for the ten HLA-A, -B, -C, -DRB1 and -DQB1 antigens, which was more frequent in 1999-2004 than in the former period (p=0.0004). In multivariate analysis, the only two factors affecting survival were HLA allelic matching (p<0.01) and younger age of recipient (17 pounds sterling years, p<0.0001). Survival reached 78%+/-11% at 5 years for the younger, fully HLA-matched patients., Interpretation and Conclusions: Survival after unrelated HSCT for SAA has improved significantly over the past 15 years, mainly due to better HLA matching. Results for young patients who are fully HLA-matched at the allelic level with their donor are comparable to those observed after HSCT from a related donor.

Background and Objectives: The treatment of acquired aplastic anemia (AA) is based on allogeneic bone marrow transplantation (BMT) and immunosuppressive therapy. The aim of this study was to assess the outcome of children and adults with AA treated in the last decade, and to determine whether results have improved in two sequential time periods,1991-1996 and 1997-2002., Design and Methods: Two-thousands and seventy-nine consecutive patients with AA, classified according to first-line treatment: BMT (n=1567) or immunosuppressive therapy (n= 912), the patients for the two sequential time periods were studied. Analyses included variables related to patients, disease and transplant., Results: The actuarial 10-year survival was 73% and 68% for BMT or immunosuppressive treatment, respectively (p=0.002). BMT outcome improved significantly with time (69% and 77%, p=001) for both matched sibling donor (MSD) (74% and 80%; p=0.003 ), alternative donor (38% and 65% p=0.0001), and was better in children (79% versus 68%, p<0.0001). Multivariate analysis: favorable predictors (p<0.001) were younger age, transplant beyond 1996, MSD, a short interval diagnosis-transplant , no irradiation. IS: no significant improvement over time (69% and 73% p=0.29). Survival was significantly better in children (81% versus 70%, p=0.001), especially in vSAA(83% versus 62%, p=0.0002). Combined IS was superior to single drug treatment (77% versus 62%, p=0.002). Multivariate analysis: significant predictors of survival: age > or =16 years (p=0.0009), longer interval between diagnosis -treatment (p=0.04), single drug versus combined IS (p=0.02)., Interpretation and Conclusions: Outcome has improved in subsets of AA patients: those receiving first- line BMT and children with vSAA treated with IS. Age remains a major predictor for both treatments. Early intervention is associated with a significantly better outcome and is strongly recommended, whatever the first-line therapy.

Background: Increased risk of transplant related mortality in male recipients of female hematopoietic stem cell grafts and in vitro reactivity of lymphocytes against H-Y encoded gene products in females with rejected male grafts have been documented. An increased rejection of male grafts in female recipients is not reported for solid organ or stem cell transplants and the role of H-Y as transplantation antigen has been controversial., Methods: Data from 1481 patients with a hematopoietic stem cell transplant for aplastic anemia reported from 154 centers in 28 countries were analyzed. Outcome was compared between patients with donors of the same or opposite sex., Results: Survival at 5 years was significantly better in patients with donors from the same sex: 68% vs. 60% (P = 0.001). Male patients with female donors had a decreased survival (relative risk of death 1.52, P < 0.001) and an increased risk of severe graft-versus-host disease (relative risk 1.33, P = 0.03) compared to recipients of sex-matched grafts. Female patients with male donors had a decreased survival (relative risk of death 1.44, P = 0.01) and an increased risk of rejection (relative risk 2.20, P = 0.01) compared to recipients of sex-matched grafts. In a subgroup analysis, the negative effects of donor/recipient sex-mismatching appeared confined to patients receiving conditioning regimens not containing antithymocyte globulin., Conclusions: These data confirm H-Y as a clinically relevant transplantation antigen, in both the graft-versus-host and the host-versus-graft direction. Wherever possible, donor-recipient sex-matching should be integrated into donor selection algorithms.

For patients with acquired severe aplastic anemia without a matched sibling donor and not responding to immunosuppressive treatment, bone marrow transplantation from a suitable alternative donor is often attempted. We examined risks of graft failure, graft-versus-host disease and overall survival after 318 alternative donor transplants between 1988 and 1998. Sixty-six patients received allografts from 1-antigen and 20 from >1-antigen mismatched related donors; 181 from matched and 51 from mismatched unrelated donors. Most patients were young, had had multiple red blood cell transfusions and poor performance score at transplantation. We did not observe differences in risks of graft failure and overall mortality by donor type. The probabilities of graft failure at 100 days after 1-antigen mismatched related donor, >1-antigen mismatched related donor, matched unrelated donor and mismatched unrelated donor transplants were 21, 25, 15 and 18%, respectively. Corresponding probabilities of overall survival at 5 years were 49, 30, 39 and 36%, respectively. Although alternative donor transplantation results in long-term survival, mortality rates are high. Poor performance score and older age adversely affect outcomes after transplantation. Therefore, early referral for transplantation should be encouraged for patients who fail immunosuppressive therapy and have a suitable alternative donor.

We have developed a reduced-intensity conditioning regimen for patients with severe aplastic anemia (SAA) undergoing alternative donor transplants, which includes fludarabine (120 mg/m(2)), cyclophosphamide (1,200 mg/m(2)) and antithymocyte globulin (7.5 mg/kg). Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine and methotrexate. We have enrolled 38 SAA patients in this trial: median age of 14 (3-37) years, transplanted from unrelated (n=33) or family mismatched (n=5) donors, with unmanipulated marrow (n=36) or peripheral blood (n=2). Seven patients (18%) had evidence of graft failure, 11% developed grade II-III acute GvHD and 27% developed chronic GvHD. The actuarial 2-year survival is 73%, with a median follow-up of 621 days. Younger patients (

From January 1978 to December 2001, 133 patients with severe aplastic anemia (SAA) underwent non-T cell-depleted allogeneic bone marrow transplantation from an HLA-identical sibling donor, at the Hospital Saint Louis using either the combination of cyclophosphamide (Cy) and thoracoabdominal irradiation (TAI; n=100) or Cy and antithymocyte globulin (ATG; n=33), as a conditioning regimen. With 13.6 years of follow-up, the 10-year survival estimate was 64%. Four factors were associated with lower survival: older age, use of Cy-TAI, any form of treatment prior to transplantation (either androgens or immunosuppressive therapy, [IST]), and grade II to IV acute graft-versus-host disease (GvHD). TAI was the sole factor associated with the occurrence of acute GvHD. The risk of cancers (15-year cumulative incidence, 10.9%) was associated with older age and with the use of cyclosporine as IST before transplantation. Cumulative incidences and risk factors of nonmalignant late effect including avascular osteonecrosis and late bacterial, viral, and fungal infection were also analyzed. Improved results using Cy-ATG as conditioning can lead to more than 90% chance of cure in patients with SAA. Even if, in our experience, the role of Cy-ATG versus that of Cy-TAI remained inextricably related to the year of transplantation, the major detrimental role of the GvHD disease in the long-term outcome and its relation to TAI supports avoidance of irradiation in the conditioning regimen. Furthermore, avoidance of any IST before transplantation in patients with a sibling donor is a prerequisite for attaining such excellent results.

To assess whether Fanconi anemia (FA) patients might be at risk for acute graft-versus-host disease (AGvHD) despite using low-intensity conditionings, we retrospectively analyzed the incidence of AGvHD and its impact on outcome in 37 FA patients and 73 patients with acquired aplastic anemia (AAA) that received transplants at Saint Louis Hospital from HLA-genotypic identical siblings with similar conditionings (thoraco-abdominal irradiation plus cyclophosphamide 20 [FA] or 150 mg/kg [AAA]). Despite being younger, FA patients had an increased risk of grades II to IV AGvHD (relative risk [RR], 2.00; P =.021), especially in younger patients (RR, 7.93; P =.014). The risks of requiring systemic corticosteroids to treat AGvHD and experiencing cortico-resistant AGvHD were significantly increased in FA patients. Although non-FA and FA patients had similar 10-year outcomes, acute and chronic GvHD had a biphasic effect on FA patient outcome with an additional cluster of lethal events starting by 5 years after transplantation. This late survival fall, restricted to FA patients, was closely related to head and neck carcinomas (15-year incidence: 53%). FA patients represent a group at risk regarding AGvHD when using irradiation-based conditionings. The impact of AGvHD on survival may not be limited to the early posttransplantation period and may be a major risk factor for head and neck carcinomas and late mortality in FA patients.

Background: Aplastic anemia may develop during pregnancy and sometimes improves spontaneously after delivery. The effects of pregnancy on aplastic anemia after immunosuppressive treatment and of aplastic anemia on the outcome of pregnancy have not been described., Objective: To determine the outcome of pregnancy and the disease course among women with aplastic anemia who received immunosuppressive therapy., Design: Retrospective multicenter study., Setting: Twelve centers participating in the European Group for Blood and Marrow Transplantation., Patients: 36 women who received immunosuppressive therapy to treat aplastic anemia., Measurements: Outcomes of pregnancy and aplastic anemia and blood counts before, during, and after delivery., Results: The 36 pregnancies resulted in 34 live births (one set of twins), 2 elective abortions, and 1 spontaneous abortion. Of the 36 pregnancies, 22 were uncomplicated and 14 involved medical complications. Seven pregnancies (19%) were complicated by relapse of aplastic anemia, and 5 patients without relapse (14%) needed transfusions during delivery. After delivery, 3 of the 7 patients who had relapse recovered spontaneously and 3 recovered after retreatment. One patient who did not respond to treatment died of aplastic anemia. A woman with aplastic anemia and paroxysmal nocturnal hemoglobinuria had a fatal cerebral thrombosis after delivery. Women with uneventful pregnancies had better prepregnancy remission status (8 complete and 11 partial remissions) and a higher median platelet count (146 x 10(9) cells/L) than did women with complicated pregnancies (2 complete remissions, 8 partial remissions, and 4 cases of paroxysmal nocturnal hemoglobinuria; median platelet count, 92 x 10(9) cells/L)., Conclusions: Successful pregnancy with normal outcome is possible in women with aplastic anemia previously treated with immunosuppression. Complications appear to be more likely in patients with low platelet counts and paroxysmal nocturnal hemoglobinuria-associated aplastic anemia.

We have analyzed 2,002 patients grafted in Europe between 1976 and 1998 from an identical twin (n = 34), from an HLA-identical sibling (n = 1,699) or from an alternative donor (n = 269), which included unrelated and family mismatched donors. The proportions of patients surviving in these three groups are, respectively, 91, 66 and 37%: major causes of failure were acute graft-versus host disease (GvHD) (11%), infection (12%), pneumonitis (4%), rejection (4%). In multivariate Cox analysis, factors predicting outcome were patient's age (p < 0.0001), donor type (p < 0.0001), interval between diagnosis and bone marrow transplantation (BMT) (p < 0.0005), year of BMT (p = 0.0005) and female donor for a male recipient (p = 0.02). Patients were then divided in two groups according to the year of BMT: up to or after 1990. The overall death rate dropped from 43 to 24% (p < 0.00001). Improvements were seen mostly for grafts from identical siblings (from 54 to 75%, p < 0.0001), and less so for alternative-donor grafts (from 28 to 35%; p = 0.07). Major changes have occurred in the BMT protocol: decreasing use of radiotherapy in the conditioning regimen (from 35 to 24%; p < 0.0001) and increasing use of cyclosporin (with or without methotrexate) for GvHD prophylaxis (from 70 to 98%; p < 0.0001). In conclusion, the outcome of allogeneic BMT for patients with severe aplastic anemia has considerably improved over the past two decades: young patients, grafted early after diagnosis from an identical sibling, have currently an over 80% chance of long-term survival. Transplants from twins are very successful as well. The risk of complications with alternative donor transplants is still high., (Copyright 2000 S. Karger AG, Basel)