Severe Acquired Aplastic Anemia Research Articles

Real-World Costs and Cost-Effectiveness Analysis of Rabbit-Antithymocyte Globulin Versus Oxymetholone in Acquired Aplastic Anemia in Thailand

ObjectivesThis study aimed to compare rabbit-antithymocyte globulin and cyclosporine (rATG/CsA) with oxymetholone in terms of direct medical expenditures and economic evaluation in severe acquired aplastic anemia (SAA) and very severe acquired aplastic anemia (vSAA) patients. MethodsPatients with SAA/vSAA who initiated treatment with rATG/CsA or oxymetholone between 2004 and 2018 were included. Trial-based cost-effectiveness evaluation in healthcare provider perspective was performed. Direct medical costs were retrieved from hospital database, inflated, and converted to 2020 US dollar (30.01 Baht per US dollar). One-way sensitivity analysis and probabilistic sensitivity analysis by nonparametric bootstrap was performed. ResultsAfter 2-year follow-up, the total mean (SD) direct medical expenditures per patient for oxymetholone and rATG/CsA group were $8 514.48 ($12 595.67) and $41 070.88 ($22 084.04), respectively. Nevertheless, oxymetholone had significant lower survival rate than rATG/CsA (P=.001) but higher in second-year blood transfusion need (71.4% vs 18.2%) and hospitalization (14.3% vs 0%). The incremental cost-effectiveness ratio was $45 854.08 per life-year gained when rATG/CsA was used instead of oxymetholone (95% CI $24 244.03-$143 496.67 per life-year gained). The probabilistic sensitivity analysis indicated that rATG/CsA had no chance of being cost-effective for SAA/vSAA when willingness to pay threshold of one to 3 times of national gross domestic product per capita was applied. ConclusionsOxymetholone remains a viable alternative in resource-limited country. Despite its high cost, the rATG/CsA is a preferred treatment option because of the significant advantages on reducing mortality, treatment complications, and hospitalization.

Ex Vivo T-Cell Receptor αβ +/CD19 +depletion of Peripheral Stem Cell Grafts for Pediatric Patients with Bone Marrow Failure (BMF) Undergoing Unrelated Donor Transplantation

Background: Success of alternative donor stem cell transplantation (SCT) for acquired and inherited bone marrow failure (BMF) syndromes has previously been limited by significant risks of severe graft versus host disease (GvHD) and graft failure, particularly for patients who lack fully HLA-matched donors. The development of post-transplant cyclophosphamide (ptCy)-based haploidentical donor SCT has mitigated but not eliminated these risks, and the relatively slow engraftment seen with ptCy bone marrow grafts may not be ideal given high rates of infectious disease and bleeding concerns in patients with BMF. Partial T cell depletion of mobilized peripheral stem cell (PSC) grafts can greatly reduce risks of graft versus host disease while facilitating rapid and robust engraftment by providing a high stem cell dose. We previously reported excellent outcomes with minimal GVHD and no graft rejection using peripheral stem cell transplant (PSCT) combined with ex vivo CD3 +/CD19 +depletion and low dose CD3+ T cell addback from matched unrelated donors (MUD) and mismatched unrelated donors (MMUD) in pediatric patients with BMF. Here, we describe the use of selective ex vivoT cell receptor (TCR)αβ +/CD19 +depletion of mobilized PSC from MUD and MMUD for pediatric patients with BMF, which has the advantage of retaining TCRgd +T cells which may help facilitate engraftment and decrease infections.Methods: We report the outcomes of 26 pediatric patients with BMF (excluding MDS-defining clonal evolution) who underwent MUD/MMUD PSCT with TCRαβ +T cell/CD19 +depletion using CliniMACS at The Children's Hospital of Philadelphia from 2017 to 2021. Patients were enrolled on a prospective clinical trial for patients with BMF (NCT03047746, n=21)or on an expanded access study (NCT03145545, n=5). Conditioning regimens consisted of thymoglobulin (9mg/kg), cyclophosphamide (100mg/kg), fludarabine (150mg/m 2), and low dose TBI (200-300 cGy) for patients with acquired BMF disorders, thymoglobulin (9mg/kg), busulfan (PK-adjusted), fludarabine (150mg/m 2), and thiotepa (10mg/kg) for patients with single lineage BMF or thymoglobulin. One patient with Fanconi Anemia received thymoglobulin and fludarabine, with reduced dosing of busulfan and cyclophosphamide. Patients undergoing MSD-BMT for BMF over a similar time period served as a comparison group for engraftment kinetics, rates of GVHD, donor chimerism, immune reconstitution, and overall survival.Results: Subjects included 18 with severe acquired aplastic anemia (SAAA), 4 with SAAA and concurrent paroxysmal nocturnal hemoglobinuria (PNH), 2 patients with acquired BMF not otherwise specified, 1 patient with DBA, and 1 patient with Fanconi Anemia. 11 patients with SAAA underwent SCT as initial therapy while 11 patients had SCT after failing previous medical therapies. Median age at diagnosis was 10.3 years (0.1-20.6) and at transplant 11.1 years (0.9-21). HLA match of unrelated donors was either 10/10 (n=15), or 9/10 (n=11). Median CD34 +and TCR αβ +T cell dose was 12.0x10 6cells/kg (3-22.6) and 0.1x10 5cells/kg (0.0-4.2). Median times to neutrophil and platelet engraftment per CIBMTR criteria were 15 days (10-22) and 15 days (13-19), respectively, both significantly earlier than engraftment following MSD-BMT (Fig 1a). At a median follow-up of 727 days (39-1498), 25 of 26 patients are alive with resolved hematologic disease (Fig 1b). One patient with SAAA+PNH who failed prior IST achieved trilinear engraftment without GVHD, but died on Day+95 due to acute disseminated toxoplasmosis. No patients exhibited immunologic graft rejection. 2/26 patients had grade II acute GVHD that responded to steroids and none developed Grade III-IV acute or chronic extensive GVHD (Fig 1c) CMV viremia/reactivation occurred in 5 subjects, all responding to antiviral pharmacotherapy, and none developed end-organ CMV disease (Fig 1d). One patient developed recipient-derived EBV post-transplant lymphoproliferative disorder requiring multimodal treatment. Only one patient developed BK cystitis. Total peripheral chimerism exceeded 90% in all patients. Immune reconstitution kinetics were similar to that seen in MSD-BMT.Conclusion: MUD/MMUD PSCT with TCRαβ +T cell/CD19 +depletion in patients with BMF enables rapid, durable engraftment with minimal risk of GVHD and immunologic graft rejection. [Display omitted] DisclosuresMonos: Omixon: Consultancy, Patents & Royalties. Grupp: Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Novartis, Kite, Vertex, and Servier: Research Funding; Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy.

Eltrombopag Rescue for Childhood Severe Acquired Aplastic Anemia after Poor Response to Immunosuppressive Treatment: A Nationwide Study on Behalf of the French Reference Center for Aplastic Anemia

▪Introduction: Thrombopoietin receptor agonist eltrombopag (ELT) provides hematologic improvement in up to 50% of adults with acquired aplastic anemia (AAA) refractory to immunosuppressive therapy (IST). However, current data for ELT efficacy and tolerance in childhood AAA is very limited.Methods: We conducted a multicenter nationwide retrospective study on behalf of the French Reference Center for Aplastic Anemia. Patients under 18 treated with ELT after IST for AAA were included. Lineage responses were defined as follows: red cells transfusion independency or hemoglobin increase of 1.5 g/dL, platelets transfusion independency or a 20 G/L increase in platelets counts, doubling of the neutrophil count or an increase above 0.5 G / L.Results: We identified 12 children (2-17 years old, mean 9.5±5.9 years) treated for severe (7) /very severe (5) AAA with horse ATG and cyclosporine as first-line treatment between 2014 and 2018 in five different centers. Minor PNH clone was identified at diagnosis in two patients. All patients had a normal bone-marrow karyotype and FISH. None had a matched related donor. Median time between IST onset and eltrombopag initiation was 3.5 months [1-46]. All patients still met severe aplastic anemia criteria and needed RBC and platelet transfusions at ELT initiation. Mean hemoglobin, reticulocytes, platelets and neutrophils values were 7.3±0.8 g/dL, 24.5±24 G/L, 11±5.9 G/L and 0.8±0.7 G/L. Seven patients had received IST for more than 3 months and were therefore considered refractory to this treatment. ELT was indicated for an uncontrolled bacterial infection in 2 patients one and two months after IST initiation. One patient received an excessive dose of 12.5 mg/kg/day. Average ELT dosage for the other patients was 2±0.6 mg/kg/d. The median duration of treatment with ELT was 5.5 months [1-10]. After ELT initiation, nine patients (75%) reached hematological response for at least one cell line with no additional treatment. In these patients, hemoglobin increased on average by 3±1.3 g/dL, neutrophils by 2.5±3.5 G/L and platelets by 89.8±39.7 G/L. Seven patients (58%) achieved a trilineage response and were both RBC and platelets transfusions independent after 1 month (1), 3 months (3) and six months (7). Five patients (41.6%) reached a robust response (platelets > 50 G/L, hemoglobin > 10 g/dL, neutrophils > 1 G/L). All these trilineage responders were still on cyclosporine at the time of last assessment. ELT was withdrawn in 4 trilineage responders. Two of them still fulfilled robust response criteria 3 and 43 months after ELT withdrawal while the 2 others required occasional transfusions. The 3 others trilineage responders who were still receiving ELT remained transfusion independent 6 (2) and 11 (1) months after ELT initiation. Two patients (16.6%) had a unique lineage response: one was lost of view and one developed a myelodysplasia with RUNX1 mutation 3 months after ELT initiation. He is alive 8 months after HSCT. No clonal evolution was reported in the 5 other patients for whom cytogenetics follow-up was available. No response was achieved in 3 patients (25%), all of whom were treated for less than 3 months: ELT was withdrawn for deemed inefficiency in 2 patients (16.6%) after 1 and 2 months respectively and for toxicity (disseminated intravascular coagulation) in another patient after 2 months. These patients underwent HSCT. One patient died of graft failure 3 months after HSCT. Overall, eleven patients (91%) were alive 13.4±5.6 months after eltrombopag onset. Disseminated intravascular coagulation occurred in a 2 years patient who received a large ELT dosage (12.5 mg/Kg). No other grade III-IV toxicity was reported.Discussion/Conclusion: This is the first report of ELT for childhood severe AAA after IST. Eltrombopag was overall well tolerated. We observed a high rate of sustained trilineage response as reported in adult patients and only 1 case of clonal evolution which is a known complication in non-responsive AAA. Onset of the trilinear hematologic responses is progressive and achieved 3-6 months after ELT initiation. A longer follow-up of this cohort is mandatory to assess response durability and clonal evolution final risk. Nevertheless, we propose that ELT should be considered for severe AAA non-responsive to IST after 3 months of treatment especially if only an alternative donor is available. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Changes in Bi-ventricular Function After Hematopoietic Stem Cell Transplant as Assessed by Speckle Tracking Echocardiography.

Hematopoietic stem cell transplant (HSCT) is a therapeutic option for patients with sickle cell disease (SCD) and severe acquired aplastic anemia (SAA). HSCT may have beneficial effects on ventricular function in damaged myocardium. We hypothesized improvement in ventricular performance and pulmonary hypertension following HSCT with strain echocardiography in SCD and SAA. Echocardiographic strain and other standard functional data were obtained via retrospective cohort analysis of patients (n=23) with SCD and SAA who underwent HSCT and were followed at a single center between 2000 and 2014. Left ventricular global longitudinal strain was below normal at baseline, and decreased significantly (from -16.6 to -11.1, P=0.05) from pre-HSCT to the initial post-HSCT echocardiogram at 109 (SD±83) days. At 351 (SD±115) days, longitudinal strain improved significantly from initial decline (from -11.1 to -17.5, P=0.009) but was comparable to baseline (P=0.43). Other measurements of bi-ventricular function did not change significantly. Tricuspid regurgitation velocities as surrogates for pulmonary hypertension improved in the subset of patients with baseline elevated values although data points were limited. Abnormal myocardial systolic function was detected at baseline with strain imaging. HSCT was associated with initial worsening longitudinal strain values, followed by improvement to baseline levels by 1year. Insufficient data exist on whether pulmonary hypertension improves after HSCT.

Fludarabine-Based Reduced Intensity Regimen for Matched Related Donor Stem Cell Transplantation in Acquired Severe Aplastic Anemia

The outcome of severe acquired aplastic anemia (SAA) has improved dramatically over the past few decades due to advances in allogeneic stem cell transplantation (allo-STC). Different conditioning regimens have been tested in matched related donor (MRD) transplants with variant results. Before 2008, we have encountered poor engraftment in our patients using high dose cyclophosphamide (200 mg/kg) and thymoglobulin (ATG). Fludarabine, low dose cyclophosphamide, ATG and total body irradiation (TBI) was used for alternative donor transplants by Bacigalubo and colleagues (1). Since 2008, we have decided to start using this regimen in our MRD transplants to improve engraftment and ultimately overall survival. To our knowledge, this abstract describes the outcome of the largest cohort of patients who received MRD allo-STC for SAA using this regimen. It represents our single institution experience over a period of 10 years.Methods: This is a retrospective chart review of all patients diagnosed with acquired SAA who underwent allo-STC between August 2005 and December 2015 at the American University of Beirut Medical Center (AUBMC)Results: A total of 22 patients underwent transplant with grafts from related HLA-matched donors. Before 2008, three patients received cyclophosphamide 50 mg/kg/day over 4 days and ATG (Fresenius) 30 mg/kg/day over 4 days. Since 2008, nineteen patients received fludarabine 30 mg/m2/day for 4 days (-6, -5, -4 and -3), cyclophosphamide 300 mg/m2/day for 4 days (-6, -5, -4 and -3) and ATG (Genzyme) 3.75 mg/m2/day for 2 days (-4 and -3). TBI at a dose of 2 Gy was added on day -1 for patients more than 15 years of age. Graft versus host disease (GvHD) prophylaxis consisted of cyclosporin A with either mycophenolate mofetil (50%) or a short course of methotrexate (50%). The median age of patients was 21 years (range: 1.7-64 years). The median duration between diagnosis and transplant was 11 months (range: 1-85 months). Seven patients (31%) had failed immunosuppressive therapy before transplant. The stem cell source was bone marrow (BM) for 14 patients (64%) and peripheral blood (PB) for 8 patients (36%). The median CD34 cell dose infused was 5.4 ×106/kg (range: 1 - 19.5 ×106/kg). The 2-year overall survival rate was 82% with trend toward better survival without statistical significance when using fludarabine-based regimen (84% vs 66%, P: 0.42), if both donor and recipient had the same gender (92% vs 66%, P: 0.11), or if PB was the source of stem cells (87% vs 78%, P: 0.58). Engraftment failure was observed in 2 cases (9%). The median time for neutrophil engraftment was 20.3 days (range: 14-38 days). Neutrophil engraftment was faster when the fludarabine-based conditioning regimen was used (18 vs 38 days, P: 0.04), if PB was used as the source of stem cells (17 vs 20 days, P: 0.03) or if TBI was added to the conditioning regimen (18 vs 20 days, P: 0.07). Chimerism studies were available for 18 out of 20 engrafted patients. Two patients had partial engraftment (89% and 76%) and 16 patients had complete engraftment (>90%). The previous use of IST or the duration between diagnosis and transplant (< or > 1 or 2 years) did not affect survival or engraftment. Acute GvHD (grade I-II) occurred in 2 patients (9%). No cases of chronic GvHD or veno-occlusive disease (VOD) were reported. CMV reactivation occurred in 2 cases while CMV disease was reported in another case. EBV reactivated in one case without LPD. Hemorrhagic cystitis occurred in one case. One patient developed donor cell precursor B-cell acute lymphoblastic leukemia 2 years after transplant.Conclusions: Fludarabine-based reduced intensity regimen for MRD transplants in SAA has led to improved engraftment with minimal toxicity. This result was not affected by the previous use of IST or the long duration between diagnosis and transplant as was reported in previous studies with different conditioning regimens or donor types. Thus, this regimen may be particulary useful in countries where patients present late to transplant.

A Retrospective Multicenter Study to Evaluate the Efficacy of Rabbit Antithymocyte Globulin (rATG) Immunosuppressive Therapy As First-Line Treatment of Aplastic Anemia

BackgroundImmunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine is the preferred treatment for patients with severe acquired aplastic anemia (SAA) ineligible for hematopoietic stem cell transplantation. In 2007, horse ATG (hATG) was removed from most markets outside the US limiting patients to the use of rabbit ATG (rATG). Response rates for hATG range from 60-70%, with overall survival (OS) rates of 60-90% (Korean J Intern Med. 2014;29:713-726). Although, many studies have shown no differences in efficacy between ATG types, others have shown rATG to be inferior to hATG. A prospective study by the US National Institutes of Health (NIH) showed a 6-month RR of 37% for rATG compared to 68% for hATG (N Engl J Med. 2011;365:430-438). The discrepancies in efficacy could be due to many factors including dose and ethnicity. We aimed to analyze hematologic response, survival, and safety of rATG (Thymoglobulin®) as first-line therapy of SAA and very SAA (vSAA) in Asian patients of all ages.MethodsWe retrospectively reviewed the medical records of 97 consecutive patients who received rATG in combination with cyclosporine and/or a corticosteroid as first-line treatment of SAA or vSAA at participating centers in Malaysia, Taiwan, Hong Kong, and Thailand between 2006 and 2012. The primary endpoint was overall RR (ORR) (complete response [CR] plus partial response [PR]) at 6 and 12 months for patients receiving rATG within the recommended dose range (2.5-3.75 mg/kg/day). Response was evaluated using British Guidelines (Br J Haematol. 2009;147:43-70). Secondary endpoints included ORR in patients receiving any dose of rATG, 2-year OS, OS in responders vs non-responders, relapse rate, and safety. Response and survival with 95% confidence intervals (CI) were estimated using the Kaplan-Meier method.ResultsPatient median age was 31 years (range 2-81 years); 51% (n= 49) were male and 49% (n=48) female. Eighty-seven percent (n=84) were diagnosed with SAA and 13% (n=13) with vSAA. Twelve patients were excluded from the response evaluation due to the following: lack of post-baseline response data, n=6; second-line rATG within 3 months of first-line treatment, n=3; did not meet criteria for SAA, n=3. Of the 85 patients evaluable for response, only 73% (n=62) received rATG within the recommended dose range; 20% (n=17) received < 2.5 mg/kg/day and 7% (n=6) received > 3.5 mg/kg/day. For patients who received rATG within the recommended dose range, 6- and 12-month ORR were 17.4% (95% CI, 9.8-30.0) and 63.6% (95% CI, 49.4-77.7), respectively. For patients who received any dose of rATG, 6- and 12-month ORR were 24.3% (95% CI, 16.2-35.4) and 68.6% (95% CI, 56.9-80.1), respectively. The 2-year OS rate was 86.3% (95% CI, 77.0-92.0). For patients with a response to treatment (n=46), the 2-year OS was 97.7% (95% CI, 84.6-99.7) compared to 78.9% (95% CI, 59.9-89.6) for patients with no response (n=39), P =.006. The 2-year rate of relapse rate was 6.3% (95% CI 2.1-18.2). The most common serious adverse events (≥ 5%) that occurred within 30 days of last treatment were febrile neutropenia (28%), sepsis (12%), pyrexia (5%), and pneumonia (5%). Grade 4 infusion-related reactions occurred in only 1 (1%) patient.ConclusionsAlthough the 6-month ORR for rATG was low compared to hATG in the NIH study, the 12-month ORR and 2-year OS were comparable to historical results obtained with hATG, suggesting that more time may be needed to achieve maximal response with rATG. Our results show that rATG is an effective form of IST in the Asian population with over 60% of patients achieving a CR or PR at 12 months and an overall survival rate of 86.3% at 2 years. DisclosuresWong:GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Merck Sharp & Dohme: Research Funding; Biogen-Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Rojnuckarin:Sanofi: Research Funding. Chang:Novartis: Honoraria.

Efficacy of Nonmyeloablative Allogeneic Hematopoietic Stem Cells for 14 Case of Severe Acquired Aplastic Anemia

To investigate the therapeutic efficacy of nonmyeloablative allogeneic hematopoietic stem cells transplantation for severe acquired aplastic anemia (SAA). Fourteen patients with severe acquired aplastic anemia received nonmyeloablative allogeneic hematopoietic stem cells transplantation from HLA matched sibling donors, among them 8 cases were dagnosed as SAA-I, 6 cases were diagnosed as SAA-II. The conditioning regimen consisted of fludarabine (FIUD), cyclophosphamide (CTX) and anti-thymocyte globulin (ATG/ALG). The prophylaxis for graft-versus-host disease (GVHD) was performed with cyclosporine (CsA) combined with mycophenolate mofetil (MMF) or tacrolimus (FK506). All the patients gained a quick successfully engraftment of donor hametopoietic cells. The mean recovery time for neutrophil and platelet was 9 d and 13 d respectively. All the patients have acquired a full donor chimerism before 14 d. There were only 2 cases of GVHD: one out of them was acute skin GVHD (grade I) at day 70 after transplantation and the other was chronic liver GVHD (grade I) in 1 years after transplantation, the GVHD more than degree II did not coccur in all patients, 9 patients with bacterial and fungal mixed infection and (or) virus infection were observed, and improved after anti-infection therapy. The median follow-up time were 54.5 months (ranged between 5-144 months), and 12 patients remain disease-free survival currently, only 2 patients died of fungal infectin. Transplantation of nonmyeloablative allogeneic hematopoietic stem cell is safe and effective for the treatment of severe acquired aplastic, but the prevention, treatment and monitoring of infection need to be enhance.

Side Effects Of Immunosuppressive Therapy(IST) Of Aplastic Anemia In Children

IntroductionAcquired aplastic anemia is very rare disease characterized by and pancytopenia and hypoplastic bone marrow. In 70% of cases the etiology is idiopathic but some cases can be caused by drugs, chemical substances and viruses. One of the main pathophysiological mechanism of aplastic anemia is immune-mediated destruction of hematopoietic cells. As a result of that the immunosuppressive therapy (IST) persists the treatment of choice in patients with severe acquired aplastic anemia (SAA), who don't have matched sibling donor. Since few last years there is a discussion if it is still the best way of treatment. We wanted to show the side effects of IST during the therapy of SAA using the rabbit antithymocyte globulin(r-ATG) MethodsThe group of 55 children ( 32 boys, 23 girls) with SAA and vSAA (very severe aplastic anemia) treated with r-ATG , steroids, CSA, and/or GSF-CS was retrospectively analyzed. The median age of the children was 10 years (range 6mth-17,5 years). Response rate was assessed on days 84, 112,180, 360. Kaplan–Meier estimator, univariate analysis and multivariate Cox regression models were used to estimate the influence of side effects for PFS (progression free survival) and EFS( event free survival). ResultsInfectious complications (fever of unknown origin-FUO-26,92%, stomatitis -19,23% and sepsis -17,03% ) were the most common side effects of IST. The most common etiology were : E. coli, P. aureginosa, S. aureus, Kl. pneumonie, E. fecium, E. cloace. There was a significant association between EFS and infectious side effects (p=0,00093- log rank). Among side effects of r-ATG fever (30,30%) and dyspnoe (24,24%) were the most common.After CSA mainly gingival hyperplasia, hirsutysm and hypertension were observed. The most common hemorrhagic side effects of IST were skin petechiae. The other were central nervous system bleeding, gastrointestinal tract bleeding. There was significant correlation between the hemorrhagic side effects and PFS(p= 0,0144 log rank).After the G-CSF therapy muscular pains, and capillary leak syndrome, was observed but it didn't influence survival. Among all patients 15 deaths was observed (27,27%)-5 early and 10 late deaths. Infections were the main causes of death. The relapse rate was 1,81%. The 2-year probability of not having relapse was 87,68%. Relapse free survival was 75,16% at 5 and 10 years. There was one transformation to paroxysmal nocturnal hemoglobinuria (PNH). There were no transformation to MDS or AML.Discussion. Infections are the most common side effects during the IST with r- ATG. Hemorrhagic side effects and infectious complications are very important factors which can affect the survival rate in children with SAA. Disclosures:Szczepanski:Octapharma AG: Investigator Other.

Are Colony Stimulating Factors (G-CSF) Still Needed in Treatment of Severe Aplastic Anemia in Children?

AbstractAbstract 4400 Objective.Allogenic bone marrow transplantation is the first choice in children with severe acquired aplastic anemia (SAA), but if there is no matched sibling donor, the immunosuppressive therapy (IST) which consists of ATG combined with cyclosporine A, steroids and/or colony stimulating factors (G-CSF), is the best way of treatment.In last two decades there was a trend to add G-CSF to combination of ATG and CSA. Nowadays there is much uncertainty about this practice. There are discussion whether it really reduces early infectious mortality. There are suggestions too, that long term using of G-CSF can play role in developing clonal disorders. Aim.The aim of this study was to assess the influence of period of using colony stimulating factors for the event free survival (EFS), and progression free survival (PFS), infectious side effects, clonality and relapses in patients with SAA. Methods.The group of 55 children with SAA and vSAA (23 girls and 32 boys,) were retrospectively analyzed. The median age of children was 10 years (range 6mth-17,5 years). IST (Thymoglobuline, steroids, CSA, and/or GSF-CS) was given according to the protocol of The European Blood and Marrow Transplant (EBMT) Severe Aplastic Anemia Working Party.G-CSF was administered at the dose of 5μg/kg/mc, in 52 patients. The median period of administration was 32 days (range 0–187 days)The response to the treatment was assessed on 84, 112,180 and 360 day. Relative risk test and Kaplan–Meier estimator, the univariate analysis and multivariate Cox regression models, test were used to estimate the influence of the period of G-CSF therapy for EFS, PFS, relapse free survival, clonality, toxicity and other side effects in children with aplastic anemia Results.The 2- year probability of event free survival (EFS) was 71,52%. The 5 and 10 –year EFS was 57,7%. Progression free survival (PFS) was 66,53%, at 2 years and 59,13% at 5- and 10 years. The relapse rate was 1,81%. The 2-year probability of not having relapse was 87,68%. Relapse free survival was 75,16% at 5 and 10 years. There was 15 deaths (27,27%), 5 early and 10 late deaths. Infections were the main causes of death. There was one transformation to paroxysmal nocturnal haemoglobinuria (PNH) and no transformation to MDS or AML. There was no significant correlation between EFS, PFS and the duration of G-CSF treatment (p > 0,05 log rank). There was tendency for longer PFS and EFS in patient who had G-CSF administered for shorter period. Relative risk (RR) for patients who didn’t receive G-CSF was connected with 28% lower infection rate. RR for children receivingG-CSF for 1–10 days was 0,55.No infectious episodes were observed in children who were treated with G-CSF for 11 – 21 days. RR for patients treated from 21 to 28 day was 1,71. Patients who were given G-CSF for more than 28 days had RR=1,15. During the G-CSF therapy we observed muscular pains, and capillary leak syndrome, but these side effects didn’t influence survival (p>0,05 log-rank) Conclusions.The duration of G-CSF therapy has no impact on the survival (EFS, PFS), but it is a significant factor concerning infection rate. Colony stimulating factor shouldn't be routinely used. Period of administration should be as short as possible. Disclosures:No relevant conflicts of interest to declare.

Matched Sibling Versus Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation in Children with Severe Acquired Aplastic Anemia: Experience of the Polish Pediatric Group for Hematopoietic Stem Cell Transplantation

In the study, 48 children with severe acquired aplastic anemia (SAA) transplanted from matched sibling donor (MSD) between 1991 and 2009, and 38 children with SAA transplanted from matched unrelated donor (MUD) between 2000 and 2009 were evaluated. Engraftment was achieved in 45 (93.75%) patients after MSD-hematopoietic stem cell transplantation (HSCT) and in 33 (86.8%) after MUD-HSCT. Transplant-related mortality rate after MSD-HSCT was 8%, while 37% after MUD-HSCT. After MSD-HSCT 44 (91.7%) patients are alive for 1-216months (median: 85months), while after MUD-HSCT 24 (63.2%) patients for 1-84months (median: 16months). The 5-year probability of event-free survival after MSD-HSCT and MUD-HSCT was 87 and 53%, respectively, while 5 years of overall survival was 91 and 64%, respectively. It was concluded that MSD-HSCT as the first line treatment for children with SAA is a safe therapeutic approach with a low rate of treatment failures and excellent outcome. Results of MUD-HSCT in pediatric patients with SAA who failed to respond to immunosuppressive therapy are still inferior than those of MSD-HSCT. Treatment failures of MUD-HSCT are mainly related to infectious complications and graft failure. It seems, however, that HLA-matching of unrelated donors at allelic level along with early MUD-HSCT after FCA (FLUDA, low-dose cyclophosphamide, and anti-thymocyte globulin) conditioning, perhaps using lower Thymoglobulin dose could enable further improvement of long-term results in children with SAA who lack MSD.

Results of Treatment of Severe Aplastic Anaemia in Children Using Rabbit Antithymocyte Globulin(r-ATG),

Abstract 3435 Objective:One of the main patophysiological mechanism of aplastic anemia (AA) is immune-mediated destruction of hematopoietic cells. In children with severe acquired aplastic anemia (SAA) allogenic bone marrow transplantation is the first choice. If there is no matched sibling donor the first line of treatment is immunosuppressive therapy (IST) which consists of ATG combined with cyclosporine A. Aim.The aim of this study was to analyze the results of IST containing rabbit anti-thymocyte globulin (r-ATG) performed on children with SAA and vSAA treated between 1996–2009 yr. We wanted to assess the influence of such factors as response to treatment, etiology, sex, age, type of AA, for: event free survival (EFS), and progression free survival (PFS) We analyzed deaths rate, relapses rate, clonality and side effects of IST. Materials and methods.We retrospectively analyzed group of 55 children with SAA and vSAA. The group consisted of 23 girls and 32 boys, the median age was 10 years (range 6mth-17,5 years). IST contained antithymocyte globulin,given intravenous at a dose of 3,75 mg/kg/day for 5 days, and cyclosporine A(CSA) at 5 mg/kg/day by mouth in divided doses started on day 1 and continued for at least 6 months(till 24 months). Response rate was assessed on 112, 180 and 360 day and defined as CR, PR, NR. Kaplan–Meier estimator, univariate analysis and multivariate Cox regression models were used to estimate the influence of such factors as response to treatment, etiology, sex, age for EFS, PFS, toxicity and other side effects. Results.Table 1Response rate at 112, 180, 360 day of ISTDays of treatmentCR N(%)PR N(%)CR+PR N(%)NR N(%)Others* N112 (55 pts)5 (9,09%)23 (41,81%)28 (50,90%)19 (34,54%)8180 (55 pts)5 (9,09%)23 (41,81%)28 (50,90%)15 (27,27%)12360 (55 pts)7 (12,72%)15 (27,27%)22 (40,00%)2 (3,63%)31*died from different causes than progression of disease, patients after II IST, patients after BMT, no information availableThe 2- year probability of event free survival (EFS) was 71,52%. The 5 and 10 –year EFS was 57,7%. Progression free survival (PFS) was 66,53%, at 2 years and 59,13% at 5- and 10 yearPatients with CR and PR had significantly longer EFS than children with no response(NR) (p<0.0001 Wilcoxon). There was no significant correlation between EFS, PFS and such factors as etiology, sex, age, severity of AA (p > 0,05 Log rank). In all group we observed 15 deaths (27,27%), 5 early and 10 late deaths. Infections were the main causes of death. The relapse rate was 1,81%. The 2-year probability of not having relapse was 87,68%. Relapse free survival was 75,16% at 5 and 10 years. There was one transformation to paroxysmal nocturnal hemoglobinuria (PNH).Non responders (4 patients) received second IST and 11 children underwent MUD-BMT. Infections were the most often side effects of IST (FUO-26,92% of infectious side effects). There was significant association found between EFS and infectious side effects. (p=0,00093 log rank) The most common adverse effects after rabbit immunoglobulin were fever (30,30%) and dyspnoe (24,24%). After CSA treatment we observed mainly gingival hyperplasia (29,16% of side effects of CSA). Most common hemorrhagic side effects were skin petechie. There was significant correlation between hemorrhagic side effects and PFS (p= 0,0144 log rank) Conclusions.1. Rabbit-ATG is an effective frontline therapy for children with SAA without familiar bone marrow donor.2.Remission achieved on day 112 seems to be constant. 3.5-year EFS seems to be stable within next 5 years.4.5-year relapse free survival seems to be constant during the next 5 years.5.Etiology, type of SAA, age and sex have no influence on the survival.)6.Infectious and hemorrhagic side effects are a very important factors affecting the survival rate in children with SAA. Disclosures:No relevant conflicts of interest to declare.

HLA-Matched Related Donor Hematopoietic Stem Cell Transplantation In 36 Pediatric Patients With Severe Acquired Aplastic Anaemia

Severe acquired aplastic anemia (SAA) is a rare disease of childhood. Matched related hematopoietic stem cell transplantation (HSCT) is the treatment of choice for pediatric patients with SAA. Immunosuppressive therapy is the alternative treatment in children with SAA who do not have a donor. We retrospectively analyzed pediatric patients who received allogeneic HSCT from HLA-matched related donors at our institution.

Treatment of acquired severe aplastic anemia in pediatric patients with immunosuppression and allogeneic stem cell hematopoietic transplant

Severe acquired aplastic anemia (SAA) is an uncommon disease of childhood. Patients with SAA receive supportive care with transfusions and timely treatment of opportunistic infections, along with specific therapies, which may be allogenic stem cell transplantation (SCT) from a matched sibling or immunosuppressive therapy (IT). To report the experience in the management of SAA. Twenty five children with acquired SAA were treated from July 1992 to September 2005. Patients with full matched sibling donors received allogenic SCT after conditioning with a cyclophosphamide containing regimen. The other patients received immune suppression with cyclosporine plus methylprednisolone (n= 18) plus ATG (n=17). All received supportive care until recovery of hematopoietic function. Those who had severe opportunistic infections at diagnosis or did not respond to two cycles of ATG were evaluated for unrelated donor SCT. Seven patients received sibling donor SCT and 18 IT, which was repeated in six. Three patients received mismatched related (1) or unrelated (2) SCT. Nineteen patients survived with a median follow up time of 4 years, 14 with full hematologic recovery. Six patients died: four due to infections after IT or SCT, one due to intracranial hemorrhage and one with secondary myelodysplasia 12 years after IT. Most children with SAA can be treated successfully with sibling donor SCT or IT. Patients without a histocompatible sibling who fail to respond to IS have a worse prognosis.

Tratamiento de anemia aplásica severa adquirida en pacientes pediátricos con inmunosupresión y trasplante alogénico de precursores hematopoiéticos

Severe acquired aplastic anemia (SAA) is an uncommon disease of childhood. Patients with SAA receive supportive care with transfusions and timely treatment of opportunistic infections, along with specific therapies, which may be allogenic stem cell transplantation (SCT) from a matched sibling or immunosuppressive therapy (IT).To report the experience in the management of SAA.Twenty five children with acquired SAA were treated from July 1992 to September 2005. Patients with full matched sibling donors received allogenic SCT after conditioning with a cyclophosphamide containing regimen. The other patients received immune suppression with cyclosporine plus methylprednisolone (n= 18) plus ATG (n=17). All received supportive care until recovery of hematopoietic function. Those who had severe opportunistic infections at diagnosis or did not respond to two cycles of ATG were evaluated for unrelated donor SCT.Seven patients received sibling donor SCT and 18 IT, which was repeated in six. Three patients received mismatched related (1) or unrelated (2) SCT. Nineteen patients survived with a median follow up time of 4 years, 14 with full hematologic recovery. Six patients died: four due to infections after IT or SCT, one due to intracranial hemorrhage and one with secondary myelodysplasia 12 years after IT.Most children with SAA can be treated successfully with sibling donor SCT or IT. Patients without a histocompatible sibling who fail to respond to IS have a worse prognosis.

Unrelated stem cell transplantation for severe acquired aplastic anemia: improved outcome in the era of high-resolution HLA matching between donor and recipient

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. 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. 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. 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.

Unrelated Allogeneic Stem Cell Transplantation for Severe Acquired Aplastic Anemia: Has Outcome Improved?.

We aimed to determine whether outcome of HSCT from an unrelated donor has improved over time for patients with severe acquired aplastic anemia (SAA) and, if so, to determine whether improvement resulted from changes in patient selection, changes in transplantation technique, or both. We thus analyzed the outcome of 89 patients (median age 17 years, range 0–52) who received such transplantations between 1989 and 2004. We compared two cohorts of patients transplanted within two successive time-periods (1989–1998 and 1999–2004) associated with probabilities (± 95% confidence interval) of 5-year survival significantly different: 29% ± 7% and 50% ± 7%, respectively (P<.01, Figure 1). Significant differences between the two cohorts concerned transplant-related, but not patient- and disease-related variables: the use of ATG and of fludarabine within conditioning and HLA matching at the allelic level for the 10 HLA-A, -B, -C, -DRB1 and -DQB1 loci (P=.0004) were more frequent in the recent 1999–2004 period. In multivariate analysis, the only 2 factors influencing survival were HLA allelic matching (P<.01) and younger age of recipient (<17 years, P<.0001). Of note, the impact of HLA matching disappeared in multivariate analysis when it was considered at the antigenic level for HLA-A, -B and -DR antigens, which underlines the importance of considering HLA matching at the allelic rather than the generic level for these transplantations. Survival reached 78% ± 11% at 5-year for the younger patients fully HLA-matched (n=14), which can be compared with survivals obtained for HLA-identical sibling transplants in similar young patients. Cumulative incidences of graft failure, grade II–IV or grade III–IV acute GVHD, and chronic GVHD were: 14% ± 4 % at 2 years, 50% ± 5 % and 24% ± 4 % at 100 days, and 28% ± 5 % at 2 years after HSCT (limited: 17% ± 4 %, extensive: 11% ± 3 %), respectively. In a competing risk analysis, allelic HLA matching - particularly incorporating HLA-C but not -DQB1 matching - but also a high cell-dose injected (> 2,6.108/kg nucleated cells, the median value of the cohort) and the use of fludarabine and/or ATG in the conditioning regimen were found as protective against graft failure and acute GVHD, respectively. Our results suggest that survival after unrelated transplantation for SAA has improved over the past 15 years, due to a better HLA matching at the allelic level for both HLA class I and class II antigens, but also to other transplant-related factors. [Display omitted]

Bone marrow transplantation (BMT) for children and adolescents with severe acquired aplastic anemia (SAA): a single center experience in 171 patients (pts) comparing two different preparatory regimens

Bone marrow transplantation (BMT) for children and adolescents with severe acquired aplastic anemia (SAA): a single center experience in 171 patients (pts) comparing two different preparatory regimens