scholarly journals Eltrombopag Combined with G-CSF and Cyclosporine Could Effect for Severe Acquired Aplastic Anemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5110-5110 ◽  
Author(s):  
Bingyi Wu ◽  
Jiahui Cai ◽  
Li Yingshi ◽  
Dong Ruihong
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Median Time ◽  
Antithymocyte Globulin ◽  
Complete Blood Count ◽  
Conflicts Of Interest ◽  
Fungal Infections ◽  
Young Patients ◽  
Severe Adverse Effect ◽  
Hematopoietic Stem

Abstract Backgroud Acquired aplastic anemia (AA) is a potential life-threatening hematopoietic stem cell (HSC) disorder resulting in cytopenia. The first line therapy for AA is HSC transplantation for young patients who have suitable donors and immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine for the remaining patients. However, about 30% of patients are refractory to IST or relapse after IST. IST with antithymocyte globulin and cyclosporine result in severe complication and mortality infection. To reduce the mortality infection and increase the response of IST for AA is still problem. Eltrombopag, a thrombopoietin mimetic, demonstrated efficacy in restoring trilineage hematopoiesis, has recently emerged as an encouraging and promising agent for patients with refractory AA. To explore the effect of eltrombopag for severe acquired aplastic anemia, we treated seven severe AA patients with eltrombopag combined with cyclosporine and G-CSF. Herein we report initial results of the eltrombopag combined with cyclosporine and G-CSF for severe AA. Methods The diagnostic of AA patient consisted of a complete blood count, a bone marrow biopsy, bone marrow karyotype analysis and assessment of a paroxysmal nocturnal hemoglobinuria (PNH) clone. Patients with SAA aged ≥18 years old who without suitable donors received eltrombopag 75mg/d, cyclosporine 6mg/kg by oral, and G-CSF 300ug/d by subcutaneous injection from diagnosis. Red blood was infused to maintained HB more than 60g/L. Platelet were infused to maintained PLT more than 20x109/L. G-CSF was administered until neutrophil count more than 1.0x109/L. Vale concentration of cyclosporine were maintained more than 100ug/ml in blood plasm and maintained two years. Eltrombopag was taper down when platelet was more than 100x109/L. Eltrombopag was given at least three months. Antibacterial was administered when patient was high fever. Posaconazole were given for fungal infections prophylaxsis. Hematologic improvements were assessed by the National Institutes of Health (NIH) response criteria for AA. Results The median age of 7 patients with SAA was 44 years old (range 19-68 yr). Full hematologic improvements were achieved in 3 patients. All patients achieved platelet and RBC infusion independence. The median time from the first eltrombopag therapy to platelet infusion independence was 35 days (range 33-46d). The median time from the first eltrombopag therapy to RBC infusion independence was 40 days (range 30-50d). Median 6 units (1200ml) (range 3-10U, 600ml -2000ml) RBC and 7 units (2.5x109/unit) platelet were infused. With median 8 months follow-up (3-12 months),3 patients are still full hematologic improvements and 4 platelet and RBC infusion independence. No severe fugual infection was observed in this group patients. ALT slightly elevate in one patient. No other severe adverse effect was observed. Conclusions Treatment of SAA patients with G-CSF、cyclosporine combined with eltrombopag is feasible and effect. Our results deserve further research and confirmation in larger samples. Disclosures No relevant conflicts of interest to declare.

The Efficacy of Rabbit Antithymocyte Globulin (Thymoglobulin®) with Cyclosporin As First-Line Treatment in Aplastic Anemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3430-3430 ◽  
Author(s):  
Seung-Hwan Shin ◽  
Seung-Ah Yahng ◽  
Sung-Eun Lee ◽  
Byung-Sik Cho ◽  
Ki-Seong Eom ◽  
...  
Keyword(s):  
Overall Survival ◽  
Aplastic Anemia ◽  
Median Time ◽  
Antithymocyte Globulin ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Published Data ◽  
First Line ◽  
Hematopoietic Stem ◽  
Free Survival

Abstract Abstract 3430 Background: Antithymocyte globulin (ATG) is the drug of choice for immunosuppressive therapy (IST) in patients with aplastic anemia (AA) unsuitable for hematopoietic stem cell transplantation. The standard ATG preparation in AA had been horse ATG because of the larger experience and the results already reported with this preparation. Due to the unavailability of the horse ATG since 2006, rabbit ATG became the only available ATG preparation in Korea. But, there are only limited data about the therapeutic efficacy of rabbit ATG as first-line IST in AA. Method: We retrospectively investigated the outcome of 58 evaluable patients among 62 patients with AA treated with IST using rabbit ATG as front line between March 2006 and April 2010 at our institution. 70.7% of enrolled patients were very severe (n=18) or severe AA (n=23). All patients received rabbit ATG (Thymoglobulin®, 2.5mg/kg per day for 5 days) with methylprednisolone and cyclosporine A. Response rate (RR) was assessed at 3, 6, 9, 12 and 18 months after IST. Results: After IST, overall RR was 27.8%, 50.8%, 52.8%, 52.8% and 56.7% after 3, 6, 9, 12 and 18 months, respectively. Complete response (CR) rates were 0.8%, 1.8%, 5.6%, 9.6% and 21.2% after 3, 6, 9, 12 and 18 months, respectively. Median time to achieve partial response (PR) and CR were 93 (range; 12∼977 days) and 381 (range; 12–614) days. Among 31 responders, 10 patients (32.3%) relapsed. Median time between response and relapse were 396 days (range; 254∼681 days). Estimated overall survival and failure free survival at 3 years from ATG treatment were 85.8% and 42.8%, respectively. Age (>45) at the use of ATG was an independent predictor of overall survival and overall response (p=0.033 and 0.027) in univariate analysis. Other factors such as disease severity, pre-ATG hematological parameters (absolute lymphocyte count and absolute reticulocyte count) were not associated with overall survival and failure free survival. Conclusion: These data indicate that rabbit ATG was as effective as horse ATG based on other recently published data. But, the response time of rabbit ATG treatment is longer than that of horse ATG treatment. Especially, more than half of patients who achieved CR required time over 1 year after ATG treatment. Rabbit ATG can be effective IST regimen comparable to horse ATG, but it takes longer time to achieve sufficient response. Disclosures: No relevant conflicts of interest to declare.

23 Years of Management: A Retrospective Review of Treatment for Aplastic Anemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1091-1091
Author(s):  
Connie M Piccone ◽  
Marie Boorman Martin ◽  
Zung Vu Tran ◽  
Kim Smith-Whitley
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Retrospective Review ◽  
Pediatric Patients ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Complete Response ◽  
Primary Objective ◽  
Hematopoietic Stem ◽  
Transfusion Independence

Abstract Abstract 1091 Poster Board I-113 Introduction Aplastic anemia (AA) is a syndrome of bone marrow failure characterized by peripheral pancytopenia and marrow hypoplasia. In the past, AA was considered to be a fatal disease; however, current therapies, including bone marrow transplantation or immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CSA), are curative in the majority of patients. IST is effective at restoring hematopoietic stem cell production, but relapse and evolution to myelodysplastic syndromes remain clinical challenges. Additionally, there is no real consensus regarding optimal CSA levels, duration of CSA treatment, or the optimal use of growth factors and their relationship to the development of clonal disease. Objectives The primary objective was to review treatment management for severe AA in pediatric patients in order to elucidate treatment differences and review morbidity and mortality as they relate to treatment variation. Study Design/Methods A retrospective review of pediatric patients treated at the Children's Hospital of Philadelphia for AA (both severe and moderate) over a 23 year period was performed. Results A total of 70 patients with AA were treated at our institution from 1985 to July 2008. Exclusions included: 6 patients who received some type of initial treatment at outside institutions, 4 patients who had missing records, and 2 patients who had a diagnosis of moderate AA. Thus, a total of 58 patient records were included in the analysis. Of the total patients reviewed, 60% were male and 40% were female. 34.5% of patients were African-American, and 57% were diagnosed in 2000 or later. The mean age at diagnosis was 9.5±5.8 years. 52% fell into the category of very severe AA based on published diagnostic criteria, 45% had severe AA, and 2 patients (3%) had moderate AA. 15.5% of patients developed AA in the setting of acute hepatitis. More than half of the patients treated with IST had a complete response (CR). The average time to CR was 15±15 months. Average duration of CSA treatment was 15±13 months and 8.6±10.7 months for growth factor. Two patients (3.5%) died, one from complications unrelated to AA and one from infectious complications post-BMT after initial IST failure. Average time to transfusion independence for all patients was 8±11 months (with a range of 0-54 months). Not surprisingly, the time to transfusion independence was significantly associated with IST failure (p=0.010). Patients who failed treatment had an average time to transfusion independence of 17±16 months as compared to those who were complete responders who had an average time to transfusion independence of 3±3 months. Additionally, there was a significant association between IST failure and CSA levels (p=0.014). Patients who had nontherapeutic CSA levels overall had an increased rate of treatment failure. Of those patients who were nontherapeutic, 56% were noncompliant with CSA administration. There was no significant association between IST failure and bone marrow cellularity (p=0.251). PNH was diagnosed in 5% of patients; there were no patients with evidence of myelodysplastic syndrome (MDS). Two of the 3 patients with PNH failed initial IST. Another 2 patients had evidence of a cytogenetic abnormality (16q deletion), but never progressed to MDS. (Note: averages presented as mean±SD) Conclusions/Methods With current IST regimens, AA is curative in the majority of pediatric patients. IST failure was associated with nonadherence to CSA treatment. For patients with confirmed clonal disease, it is possible that IST failure and the ultimate development of clonal disease are related. Disclosures No relevant conflicts of interest to declare.

Allogeneic Transplant In Children with Severe Aplastic Anemia – Excellent Outcomes with the Use of a Fludarabine Based Conditioning Regimen

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3519-3519
Author(s):  
Biju George ◽  
Vikram Mathews ◽  
Auro Viswabandhya ◽  
Aby Abraham ◽  
Lakshmi M Kavitha ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Median Time ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Antithymocyte Globulin ◽  
Conditioning Regimen ◽  
Allogeneic Transplant ◽  
Graft Versus Host ◽  
Primary Graft Failure

Abstract Abstract 3519 There is limited data on the use of fludarabine based conditioning regimen in children with aplastic anemia though these regimens are increasingly being used in developing countries. Thirty four children (aged < 15 years) including 21 males and 13 females with a median age of 8 years (range: 2–15) underwent allogeneic transplant (HSCT) at our centre between 2004 and 2010 using HLA identical sibling or family donors. The median time from diagnosis to HSCT was 5 months (range: 2–96) and the median number of transfusions prior to HSCT was 10 (range: 3– 64). Five patients (14.7%) had failed treatment with Antithymocyte globulin (ATG) and 4 (11.4%) had an intracranial bleed in the 3 months prior to HSCT. Conditioning regimen consisted of Fludarabine 150 mg/m2 over 5 days and Cyclophosphamide 120 mg/kg over 2 days. Antithymocyte globulin (ATGAM) [10 mg/kg/day for 4 days] was used in 9 patients. Graft source consisted of either bone marrow [9 patients] or G-CSF stimulated peripheral blood stem cells (PBSC)[25 patients]. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine and short course methotrexate. The median cell doses infused were 4.9 × 108 TNC/Kg for bone marrow and 8.5 × 108 MNC/Kg for PBSC. Thirty patients (88.2%) engrafted while 2 (5.8%) had primary graft failure. Two children died on Day 0 and Day +5 respectively due to infection. The median time to neutrophil engraftment was 14 days (range: 8–19) while the median time to platelet engraftment was 12 days (range: 7–24). Two patients (5.8%) developed veno-occlusive disease (VOD) of the liver while none developed hemorrhagic cystitis. Acute graft versus host disease (GVHD) was seen in 7 patients (23.3%) and was grade 1–2 in all patients. Chronic GVHD was seen in 31% of patients who could be evaluated and was limited in nature in a majority of patients. Of the 2 patients with primary graft failure, one was rescued with a second transplant while the second expired due to fungal pneumonia. The Day 100 mortality was 14.1%. Secondary graft failure was seen in 1 patient but was rescued with a second transplant using the same donor. At a median follow up of 30 months (range: 1 –67), 29 patients are alive for a 3 year OS of 85.1%. Fludarabine based conditioning regimens are associated with favorable outcomes in Indian children with aplastic anemia. These results are superior to an OS of 37% with the use of ATG and Cyclosporine in a similar population (George B et al PHO March 2010). Disclosures: No relevant conflicts of interest to declare.

Intra-Bone Marrow Transplantation of CD34+ Enriched Grafts Following a Non-Myeloablative Conditioning Allows Successful Engraftment In DLA-Identical Canine Litters.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3711-3711 ◽  
Author(s):  
Anne Knueppel ◽  
Doreen Killian ◽  
Sandra Lange ◽  
Heike Vogel ◽  
Iris Lindner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Injection Site ◽  
Complete Blood Count ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Buffy Coat ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Application Techniques ◽  
Recovery Times

Abstract Abstract 3711 Introduction: Successful engraftment following transplantation of hematopoietic stem cells (HSCT) depends mainly on pre- and posttransplant immunosuppression, graft type and composition as well as on the HSC numbers infused. Whereas some of the aforementioned parameters can be influenced in the clinical setting, the latter one is more difficult to address. HSCTs of grafts with limited HSC numbers are accompanied by increased graft failure rates, longer cytopenias and increased morbidity. Current concepts to overcome low HSC numbers include the combination of two unrelated grafts, expansion techniques, modification of the graft composition or the site of graft infusion. In preliminary rodent studies intra-bone marrow (IBM) compared to intravenous (IV) HSCT led to faster engraftment which might be explained by closer location of the HSC to the stem cell niches. Aims: To investigate the feasibility and efficiency of IBM-HSCT following a non-myeloablative conditioning regimen in a dog-leukocyte antigen (DLA) identical canine HSCT model. Method: DLA-identical siblings were used as donor/recipient pairs for HSCTs. Recipients received a single dose of 2 Gy total body irradiation before HSCT (day 0). Pre- and postgrafting immunosuppression consisted of CSA (d-1 to d+35) and MMF (d0 to d+27). Two IBM-HSCT cohorts were investigated and data compared to IV controls (CON). BM-grafts of the respective donors were infused unmodified IV (CON, n=9) or IBM after HSC enrichment using a buffy coat followed by ficoll density centrifugation (IBM-I, n=6; 5ml total volume) or IBM after HSC enrichment using buffy coat centrifugation only (IBM-II, n=6; 25 ml total volume). In the CON group the graft was infused in the cubital vein. In the IBM-groups the grafts were infused through a BM aspiration needle into the BM of the left humerus and femur over a period of 5 minutes. In 4 IBM animals graft migration analyses were performed using technecium99 marking. Chimerism and BM cellularity were determined at injection and opposite sides. Analyses of chimerism were performed via polymorphic nucleotide repeat analyses weekly. BM cellularity was determined biweekly. Complete blood count was performed daily. Result: Infusion of grafts directly into the BM was feasible: both volumes (5ml, 25ml) could be infused without any leakage at the injection sites. Tc99-marked BM cells stayed predominately at the injection site for the first 24 hours. All animals engrafted. Mean TNC numbers infused were 2.6 ×108/kg (range: 1.6–11.4; CON), 1.6 ×108/kg (range: 1–2.4; IBM-I), 3.7 ×108/kg (range: 2.1–5.8; IBM-II) (IBM-I vs CON: p=0.08, IBM-II vs CON: p=0.9, IBM-I vs II: p<0.02,). Mean CD34+ numbers infused were 0.6 ×106/kg (range: 0.3–2.2; CON), 2.5 ×106/kg (range: 0.3–6.4; IBM-I), 4.3 × 106/kg (range: 1.3–6.5; IBM-II) (IBM-I vs CON: p=0.06, IBM-II vs CON: p=0.01, IBM-I vs II: p=0.4). PBMC chimerisms at d+14, d+28 and d+56 were 25% (range: 8–46), 36% (range: 5–63), 28% (range: 4–54) (CON), 12% (range: 6–18), 23% (range: 14–39), 18% (range: 6–64) (IBM-I) and 40% (range: 23–60), 61% (range: 31–84), 45% (range: 25–70) (IBM-II) (IBM-I vs CON: p=0.03, p=0.05, p=0.1, IBM-II vs CON: p=n.s. (all), IBM-I vs II: p=0.06, p=0.04, p=0.1). Recovery of hematopoiesis occurred significantly slower in both IBM-BMT groups compared to CON (p<0.002): mean leukopenia (<1.0 gpt/l) durations were 4 days (range: 0–15; IBM-I), 0.5 days (range: 0–2, IBM-II) versus 0 days (CON); mean thrombocytopenia durations (<50Gpt/l) were 19 days (range: 2–49, IBM-I), 10 days (range: 8–16, IBM-II) versus 4 days (range: 0–6, CON). However, if only grafts with <2.0 ×106 CD34+/kg were analysed differences concerning leukocytes recovery times diminished between IBM and the IV groups, whereas they persisted in regards to thrombocytopenia. Analyses of cellularity and chimerism within a HSCT recipient (injection vs opposite site) revealed higher initial cellularities and significantly higher BM donor chimerisms up to day +56, both in favour of the injection site (p<0.03). Conclusion: Infusion of HSC grafts up to volumes of 25ml directly into the BM is feasible and allows successful donor engraftment following non-myeloablative conditioning. Duration of cytopenias following IBM-HSCT is still significant, perhaps due to the loss of precursor cells during graft preparation. Further studies are warranted to determine optimal graft preparation and IBM application techniques. Disclosures: No relevant conflicts of interest to declare.

Genetics in Inherited Bone Marrow Failure Disorders

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-1-SCI-1
Author(s):  
Sioban Keel
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Accurate Diagnosis ◽  
Cell Transplant ◽  
Medical Monitoring ◽  
Hematopoietic Stem ◽  
New Genes ◽  
Increased Risk

The classical Inherited Bone Marrow Failure Syndromes (IBMFS) such as Fanconi anemia, Dyskeratosis Congenita, Shwachman-Diamond syndrome, and Diamond-Blackfan anemia are a heterogeneous group of disorders, all of which are characterized by impaired hematopoiesis, varying degrees of peripheral cytopenias and marrow hypoplasia and dysplasia. Many of these are associated with an increased risk of clonal dominance and evolution to myelodyplastic syndrome (MDS) and acute myeloid leukemia (AML). For the purposes of this talk, the familial MDS and acute leukemia predisposition syndromes are also included in the broad term IBMFS. The genes responsible for a subset of IBMFS have been identified and will be reviewed. However, the causative mutations in many patients presenting with seemingly inherited marrow failure remain unknown. Gene discovery in IBMFS has been difficult in large part due to the phenotypic heterogeneity of these syndromes. Some patients with IBMFS display a distinct clinical phenotype with associated syndromic abnormalities, others are variable and overlap with one another or with acquired MDS or idiopathic acquired aplastic anemia, and additional cases are more obscure and have evaded classification altogether. Accurate diagnosis of IBMFS inform patient care as it allows appropriate screening of siblings to avoid choosing an affected donor if marrow transplant is indicated and the selection of an appropriate transplant conditioning regiment to avoid undue toxicity. Additionally, accurate diagnosis allows appropriate medical monitoring and early intervention to successfully treat disease-specific non-hematologic medical complications. The application of next generation sequencing approaches for comprehensive genetic screening of IBMFS, including these cryptic or atypical presentations will be reviewed. In addition to providing accurate diagnoses in a subset of patients, genetic characterization in small family kindreds or even in single individuals presents unique opportunities to discover new genes and pathways contributing to dysfunctional hematopoiesis and clonal progression. The frequency of inherited mutations in known IBMFS genes among seemingly idiopathic acquired aplastic anemia patients or pediatric and younger adults with MDS referred for hematopoietic stem cell transplant will be reviewed. Future genetic studies are needed to characterize the secondary genetic events that lead to disease progression in IBMFS. Disclosures No relevant conflicts of interest to declare.

Natural History of Paroxysmal Nocturnal Hemoglobinuria Clones In Patients Presenting as Aplastic Anemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4428-4428
Author(s):  
Jeffrey J Pu ◽  
Galina Mukhina ◽  
Hao Wang ◽  
William Savage ◽  
Robert A Brodsky
Keyword(s):  
Bone Marrow ◽  
Natural History ◽  
Aplastic Anemia ◽  
Median Time ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Clone Size ◽  
Hematopoietic Stem ◽  
History Of ◽  
Pnh Clone ◽  
Ldh Value

Abstract Abstract 4428 Introduction: Acquired aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are closely related bone marrow failure disorders. Most AA results from an autoimmune attack directed against hematopoietic stem/progenitor cells. PNH originates from a multipotent hematopoietic stem cell (HSC) that acquires a PIG-A mutation. The PIG-A gene mutation leads to glycosylphosphatidylinositol-anchor protein (GPI-AP) biosynthesis deficiency and subsequent hemolysis secondary to the absence of complement regulatory proteins (CD55 and CD59). Both PNH and AA can be cured by allogeneic bone marrow transplantation (alloBMT), but only a minority of patients is offered this approach due to the potential morbidity and mortality. AA can be treated with immunosuppressive therapy (IST) and PNH can be controlled by eculizumab. It has been estimated that more than 50% of AA patients harbor small, but expandable PNH populations at diagnosis. The natural history of PNH clones in AA patients following non-transplant therapy is not well studied. The purpose of this study is to determine the fate and clinical relevance of these PNH clones in patients with AA who did not receive an alloBMT. Patients and Method: Twenty-seven patients with AA and a detectable PNH clone were monitored for a median of 5.3 years (range,1.5 to 11.5 years). The PNH granulocyte clone sizes were measured using flow cytometry and analyzed via CellQuest software. PE-conjugated anti-CD15 and fluoresceinated aerolysin variant (FLAER) staining were used to define granulocytes and GPI-AP deficient cells respectively. Serum lactate dehydrogenase (LDH) value was used as a surrogate for monitoring hemolysis and 1.5× the upper limit of normal LDH value (330mg/dL) as a cut-off point to define clinically apparent hemolysis. A PNH size change <2.5% was considered as stable. Patients were treated with IST, HiCy, or both. Result: We found a linear relationship between PNH granulocyte clone size and LDH values (Pearson correlation coefficient=0.73; P<0.0001). A PNH clone size above 23% was the threshold to identify hemolysis as measured by LDH (ROC analysis with AUC=0.88). Higher LDH values over the period of follow-up were associated with larger PNH granulocyte clone size at diagnosis (P=0.03). Patients with small (≤15%) initial PNH granulocytes had lower LDH levels at 5 years after diagnosis (mean±SD: 236.9±109.9 vs 423.1±248.8; P=0.02), and were less likely to develop hemolysis (13.3% vs 55.6%, P=0.06) comparing to those with larger (>15%) initial PNH granulocytes. Of 9 patients who initially were treated with traditional IST (ATG, CsA, and prednisone), 7 did not respond to treatment and eventually received high-dose cyclophosphamide (HiCy) salvage therapy, 2 achieved a remission and did not require further treatment though one demonstrated PNH clone size expansion to 50% after 37 months. After HiCy salvage, all 7 patients became transfusion independent and 4 of them had no further PNH clone expansion. PNH clone expansion was observed in 7 of 9 patients at a median time of 3 (range: 2 to 87) months after treatment. Of 15 patients who received HiCy as initial therapy, 14 achieved remissions. Later expansion of PNH size was observed in 7 patients, of which 5 eventually required intermittent blood transfusion but only 1 developed symptomatic hemolysis necessitating eculizumab therapy. The median time to PNH granulocyte clone expansion after HiCy was 52 (range: 18 to 106) months. In 5 patients who received HiCy and then relapsed, their PNH clone size only increased (1±0.7)% in (71±31) months observation during post treatment remission; however, their PNH clone size increase accelerated to (38±14)% in (34±21) months after AA relapse (P=0.04). Two nSAA patients with an initial PNH clone size ≤15% spontaneously recovered hematopoiesis at 84 and 56 months respectively, neither had PNH clone size expansion. In this study, 25.9% patients kept a stable PNH size, 48.1% patients increased the size, and 26% patients decreased the size. The group with small initial PNH clone sizes (≤15%) was the most stable over time. Conclusion: The risk of developing clinically significant PNH over 10 years appears to be low in AA patients with PNH clones, especially for those with small initial PNH granulocyte clones (≤15%) and for those who maintain remission following therapy. Disclosures: No relevant conflicts of interest to declare.

Chronic Infection Drives Hematopoietic Stem Cell Exhaustion through Differentiation and a Lowered Threshold for Apoptosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2406-2406
Author(s):  
Katie A Matatall ◽  
Mira Jeong ◽  
Sun Deqiang ◽  
Claudine Salire ◽  
Katherine Y. King
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Aplastic Anemia ◽  
Chronic Infection ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Terminal Differentiation ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Risk Of Death

Abstract Background: While inflammation is necessary to fight infection and repair damaged tissue, excessive inflammation can cause bone marrow suppression and promote cancer. In an extreme example, high levels of the inflammatory cytokine interferon gamma (IFNg) deplete hematopoietic stem cells (HSCs), resulting in aplastic anemia. Patients with this dangerous disease are pancytopenic and therefore at high risk of death from infection. Pancytopenia also occurs to a lesser extent in other inflammatory conditions such as chronic infections (tuberculosis, HIV), and autoimmune diseases (hemophagocytic histiocytosis). However, the mechanism by which HSCs are damaged by IFNg remains poorly understood. We used a mouse model of Mycobacterium avium infection to study the effects of sustained IFNg exposure on primitive hematopoiesis. In prior work, we found, surprisingly, that IFNg promotes division of quiescent HSCs. We hypothesized that cell division might lead to loss of HSCs through terminal differentiation, displacement, or activation of p53-dependent apoptosis pathways. Objective: We sought to determine whether prolonged IFNg stimulation would lead experimentally to exhaustion of the HSC compartment, and to determine the mechanism of inflammation-mediated HSC loss. Methods: We conducted repeated monthly infection of C57Bl/6 WT mice with 2 x 106 cfu M. avium, thereby generating a sustained chronic IFNg response. We characterized the blood and bone marrow of treated mice by histology, flow cytometry, colony forming assays, and bone marrow transplant. Results: Mice infected with M. avium became anemic and leukopenic after 6 months of repeated infection. High IFNg levels were sustained in the mice, with evidence of IFNg production by T cells and NK cells in the bone marrow. The number of committed hematopoietic progenitors gradually decreased and HSCs were depleted in the bone marrow by four months following initial infection, without evidence of extensive myelofibrosis. The marrow was hypercellular with a significant increase in granulocytes. Meanwhile, the myeloid differentiation capacity of the marrow was reduced, consistent with terminal differentiation of myeloid-biased HSCs, as we have previously described. Despite an overall reduction in HSC number, the HSCs that remained in chronically infected animals mostly retained their self-renewal potential, with subtle self-renewal defects evident only after two rounds of transplantation. Homing of HSCs from infected animals was not impaired, but ex vivo culture and apoptosis assays indicated that HSCs from chronically infected animals had reduced colony forming ability and were more prone to cell death upon secondary stress. These findings were recapitulated by introduction of recombinant IFNg alone. RNAseq profiling of HSCs from infected and control animals reflected increased proliferation and differentiation during infection, consistent with the above findings. Conclusions: We have established a novel mouse model of bone marrow failure related to chronic IFNg stimulation. We demonstrate that chronic infection can deplete the HSC pool by promoting HSC differentiation and lowering the threshold for apoptosis. These mechanisms may drive marrow suppression in patients with aplastic anemia, hemophagocytic histiocytosis (also associated with high IFNg levels), and patients with marrow failure associated with chronic infection. Furthermore, since a reduction in HSC number results in depletion of clonal heterogeneity, our findings have significant implications regarding the mechanism by which chronic inflammation can contribute to the emergence of clonal hematopoiesis and hematologic malignancies with age. Disclosures No relevant conflicts of interest to declare.

Treatment and Outcome of the Patients with Donor-Type Aplasia after Bone Marrow Transplantation in Children with Aplastic Anemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4782-4782 ◽  
Author(s):  
Kumhee Jeong ◽  
Joo Hyun Cho ◽  
Kyeong Ryeol Cheon ◽  
Hae In Jang ◽  
Hee Jo Baek ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Aplastic Anemia ◽  
Graft Failure ◽  
Conflicts Of Interest ◽  
Graft Function ◽  
Cell Number ◽  
Hematopoietic Stem ◽  
Stem Cell Rescue ◽  
Donor Type

Abstract Hematopoietic stem cell transplantation (HSCT) from an HLA-matched donor is the treatment of choice for children with aplastic anemia (AA). However, graft failure (GF), either primary or secondary, remains an important and life-threatening complication. Recently, donor-type aplasia, defined as bone marrow aplasia with full donor chimerism among secondary GF, has been identified after HSCT. Clinical characteristics of donor-type aplasia after HSCT and its treatment and outcome in children with AA were retrospectively reviewed. Forty-two children with AA underwent allogeneic HSCT with 10-year overall survival rate of 85.7%. While primary GF developed in 1 (2.4%), secondary GF was seen in 12 at a median of 8 months (range: 2.0-28.5 months). Among them, 11 developed a donor-type aplasia with the cumulative incidence of 26.2%. Low infused cell number (P=0.002), immunosuppressive therapy (IST) prior to HSCT (P=0.003) and preceding transfusion >40 times (P=0.008) were associated with the development of donor-type aplasia. The survival of patients with donor-type aplasia was 81.8%. Six patients were treated with stem cell rescue as follows: peripheral blood stem cell (PBSC) boost, 3; PBSC boost followed by secondary HSCT, 2; and secondary HSCT, 1. All but 1 who had a longest interval from 1st HSCT to stem cell rescue (54.4 months) showed restoration of graft function. The remaining 5 patients were managed with conservative measures including transfusions. No one showed spontaneous improvement with the median follow-up of 30.1 months (range, 4.2 to 43.0 months). Two patients died of graft failure and infection. Altogether, 4 patients still remain transfusion-dependent. Donor-type aplasia after HSCT for AA is not uncommon. Stem cell rescue, either with PBSC boost or secondary HSCT after conditioning should be attempted to obtain sustained graft function. For those who do not have availability for stem cell rescue, a novel treatment, such as thrombopoietin receptor agonist, should be considered for the future. Disclosures No relevant conflicts of interest to declare.

scholarly journals Successful Result of 113 Patients for Refractory/Recurrent Leukemia By Allogeneic Hematopoietic Cell Transplantation and Prophylactic Immunotherapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5856-5856
Author(s):  
Jingbo Wang ◽  
Xiaojun Huang ◽  
Ying Hu ◽  
Song Xue ◽  
Haoyu Cheng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Transplantation ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Hematopoietic Stem ◽  
Prolymphocytic Leukemia ◽  
Significant Difference

Abstract Objective: To retrospectively evaluate the results of allogeneic hematopoietic stem cell transplantation for Refractory/Recurrent leukemia. Methods: From July 2012 to May 2016, total 113 patients with Refractory/Recurrent leukemia were enrolled, including 31 cases of ALL, 73 cases of AML and 8 cases of CML-BP, 1 case of Prolymphocytic leukemia. The average leukemia burden was 51% (10-99) in bone marrow before conditioning. Myeloablative conditioning regimens consisted of 13 cases of BuCy, 47 cases of TBI/FLAG, 28 cases of TBI/Cy, and 16 cases of FLAG that followed by reduced-intensified BUCY, 9 cases of CLAG/BuCy. Transplant types included sibling HLA-identical allo-HSCT (n=22) and relative HLA-haploidentical HSCT (n=91). All patients received cyclosporine A, MMF and methotrexate for GVHD prophylaxis. Analyzed outcomes were hematological engraftment, incidence of acute and chronic GVHD, incidence of CMV/EBV infecton, incidence of relapse, and nonrelapse mortality (NRM), Overall survival (OS) and Disease-free survival (DFS). Results: The median mononuclear cells and CD34+ for transfusion were 8.83 (7.02-11.64) ×108/Kg and 2.91 (0.8-8.32) ×106/Kg. 111 patients achieved stable engraftment, 2 patients died of infection before engraftment. The median time of ANC≥0.5×109/L was 16 days(8-29) and the median time of platelet ≥20×109/L was 22 days (8-150). On day 28postallogeneic transplant, 110 patients were in complete remission of bone marrow, 1 patient was in hematologic relapse. Immunity residue were negative in 107 patients and positive in 4 patients. 62 patients developed acute GVHD, the accumulative incidence of aGVHD was (57.6±4.8)%, the accumulative incidence of II-IV grade aGVHD was (47.2±4.8)%, and the accumulative incidence of III-IV grade aGVHD was (25.2±4.1)%. 62 patients developed cGVHD (43 patients extensive, 19 patients limited), the accumulative incidence of cGVHD was (70.2±6.6)% and for extensive type, the accumulative incidence was (43.6±5.2)%. The accumulative incidence of CMV infection was (42.3±4.7)%, and the accumulative incidence of EBV infection was (4.5±2)%. 10 patients developed virus cystitis, and the accumulative incidence was (9.1±2.1)%. The median follow-up time post transplantation was 10 months (1-46), 35 patients occurred hematologic relapsed and the accumulative incidence of relapse was (39.7±5.9)%. For AML, ALL and CML-BP patients, the accumulative incidence of relapse were (33.8±6.9)%, (56.6±11.7)% and (25±15.3)%respectively (p>0.05). On median follow up (10 months), 49 patients died and 64 patients survived. The cause of death included relapse (28 cases), infection (6 cases), GVHD (11 cases) diffuse alveolar hemorrhage (2cases), radiation enteritis (1 case), and TMA (1 case).Among 64 survirors, two-year accumulative incidences of OS were (49.3±5.7)%, and two-year accumulative incidences of LFS were (45.1±5.4). The two-year accumulative incidences of OS for AML, ALL and CML-BP patients were ( 52.4±7.1)%, (28.1±9.7)%,and (87.5±11.7)%respectively (p>0.05). The two-year accumulative incidence of LFS for AML, ALL and CML-BP patients were (49.8±6.5)%, (24.7±9.1)%, and (70±18.2)%respectively (p>0.05). Incidence of relapse, OS and LFS were similar in different conditioning cohorts (p>0.05). There was no significant difference in the incidence of relapse, OS and LFS over two years among patients with C-Kit, FLT3, MLL and without such genes(p>0.05). There is significant difference in incidence of relapse, OS and LFS among patients with different leukemia burdens(p<0.01). Patients with leukemia burden at 10-19% has lower relapse rate but higher OS and LFS compared to patients with leukemia burden at 80%. Incidence of relapse, OS and LFS for the prophylactic immunotherapy cohort were 32.9%, 61.1% and 57.6% respectively, compared to 45.2%, 35.8% and 35% for non prophylactic immunotherapy cohort (p<0.01). Incidence of relapse , OS and LFS for the cGVHD cohort were 12.9%, 68.4% and 66.2% respectively, compared to 78.7%, 13.9% and 12.8% for non cGVHD(p<0.01). Incidence of relapse , OS and LFS for extensive cGVHD cohort were 12.3%, 62.1% and 61.8% respectively, compared to 58.8%, 31.4% and 31.2% for non extensive cGVHD(p<0.01) Conclusion: Our clinical results have shown that the salvaged HSCT is a promising modality for treatment of Refractory/Recurrent leukemia. Especially for Refractory/Recurrent AML and CML-BP. Disclosures No relevant conflicts of interest to declare.

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