Immunosuppressive Therapy with Antithymocyte Globulin and Cyclosporine for Fulminant Aplastic Anemia.

Abstract Abstract 2364 Background: Survival after immunosuppressive therapy (IST) for aplastic anemia (AA) depends on disease severity, which is classified according to polymorphic neutrophil (PMN) count as follows: nonsevere AA (nSAA; PMN > 0.5 × 109/L); severe AA (SAA; PMN 0.2 – 0.5 × 109/L); and very severe AA (vSAA; PMN < 0.2 × 109/L). Although patients with fulminant AA, defined as PMN = 0 for > 2 weeks, generally have poor outcome, no data are available for a large cohort. Therefore, we evaluated the outcome of children with fulminant AA who were enrolled in an AA-97 study and received ATG, cyclosporine, and granulocyte colony-stimulating factor (G-CSF). Patients and Methods: A total of 288 children newly diagnosed with AA (median age, 8 years) were enrolled into an AA-97 study between 1997 and 2006 and treated with a combination of horse antithymocyte globulin (Lymphoglobulin®) and cyclosporine. For patients with PMN < 0.2 × 109/L, G-CSF was added. Patients were classified into 3 groups according to disease severity as follows: fulminant (PMN 0, n = 35); vSAA (PMN 0 – 0.2 × 109/L, n = 129); and SAA (PMN 0.2 – 0.5 × 109/L, n = 124). Of the 35 patients with fulminant AA, 8 had a history of acute hepatitis at the time of diagnosis. One case was considered to be drug-induced AA. The remaining 26 patients had unknown etiology. We evaluated the response rate (RR) at 6 months, 5-year overall survival (OS), and 5-year failure free survival (FFS). Treatment failure was defined as death due to any cause, a requirement for a secondary therapy, relapse, clonal evolution to myelodysplastic syndrome/acute myelocytic leukemia, and paroxysmal nocturnal hemoglobinuria. Results: The children with fulminant AA showed a significantly lower RR than those with vSAA and SAA (40.0%, 62.8%, and 64.5%, respectively; p =.023). Of the 20 non-responders in the fulminant AA group, 11 were rescued by alternative donor stem cell transplantation, and 5 achieved a late response after 6 months. As a result, no significant difference was noted in 5-year OS and 5-year FFS among the children with fulminant AA, vSAA, and SAA (88.5%/48.2%, 95.8%/65.1%, and 96.8%/68.1%, respectively). Conclusion: In consideration of favorable OS, the choice of IST is indicated in children with fluminant AA who lack an HLA-matched family donor. Disclosures: No relevant conflicts of interest to declare.

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Long-Term Clinical Outcome of Children with Acquired Aplastic Anemia in Brazil.

Blood ◽

10.1182/blood.v114.22.4216.4216 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4216-4216

Author(s):

Marlene Pereira Garanito ◽

Vicente Odone Filho ◽

Marcela Vieira dos Santos ◽

Elvira Velloso ◽

Frederico L. Dulley ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Cell Transplantation ◽

Survival Probability ◽

Conflicts Of Interest ◽

Time History ◽

Hematopoietic Stem ◽

Significant Difference

Abstract Abstract 4216 Introdution/ Backgound Acquired Aplastic Anemia (AAA) is a rare hematologic disorder characterized by pancytopenia and hypocelular bone marrow. The pathophysiology is immune mediated in most cases. Environmental exposures to drugs, viruses and toxins, are thought to trigger the aberrant immune response in some patients. However, 50 to 74 percent of cases are classified as idiopathic. The highest frequency occurs in young population (15 to 25 years) with a second peak at age of 65 to 69 years. Immunosuppressive therapy is the best treatment in children with AAA who do not have a suitable donor for allogeneic stem cell transplantation. Materials and methods We reviewed the medical records of patients diagnosed with severe (SAA) and very severe acquired aplastic anemia (vSAA) at the Department of Pediatrics, Instituto da Criança – Hospital das Clínicas, University of Sào Paulo, Brazil from December, 1992 to December, 2007. We analyzed the clinical characteristics of the patients at diagnosis and the response to immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT). Results In this study, 47 patients (27 boys and 20 girls), younger than 16 years, were diagnosed with vSAA (n= 21) or SAA (n=26). The median age was 7,71 years, ranging from 0.5 to 16 years and the average time history (beginning of signs and symptoms related to the disease and diagnosis) of the disease was 4,82 months, ranging from 0,25 to 48 months. Of the 47 patients, 45 had idiopathic AAA and 2 had hepatitis-associated. The median follow-up was 6,91 years for the patients treated with IST and 3,10 years for the patients who underwent to HSCT. One patient died before any treatment. For the eight patients who underwent to allogenic HLA-matched HSCT the 5-years-survival probability was 50%. For the 38 patients treated with IST, ten of them received cyclosporine and a short course of corticosteroids (CsA/CE) and 28 received antithymocyte globulin plus cyclosporine (ATG/CSA). The 5 years survival probability was 40% and 55%, respectively (p:0,0054). According to the severity of AAA, we did not show a significant difference in survival (p:0,32). Eight patients received second treatment after 1 year and 6 months (6 ATG from different species and CsA, 1 CsA and 1 thalidomide) and the probably of survival at 5 years was 60%. Among the 18 patients who responded to IST, four relapsed (22%). Two patients developed acute myeloid leukemia at 5 and 12 years after diagnosis. Conclusion Our results both for patients undergoing HSCT, as well as patients undergoing IST are lower in comparison to other hematological centers. Probably, this discrepancy is related to the prolonged time of disease when patients are admitted to our service. Unfortunately, the difficulty of access to specialized centers for diagnosis and early treatment in our country is a reality and this fact contributes to the delay to the beginning of treatment. Disclosures: No relevant conflicts of interest to declare.

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Comparison of Clinical Outcome Between Children with Aplastic Anemia and Refractory Cytopenia of Childhood Who Received Immunosuppressive Therapy with Antithymocyte Globulin and Cyclosporine

Blood ◽

10.1182/blood.v118.21.53.53 ◽

2011 ◽

Vol 118 (21) ◽

pp. 53-53 ◽

Cited By ~ 1

Author(s):

Asahito Hama ◽

Hideki Muramatsu ◽

Masafumi Ito ◽

Masahiro Tsuchida ◽

Hirotoshi Sakaguchi ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Antithymocyte Globulin ◽

Clonal Evolution ◽

Severe Disease ◽

Cell Lineage ◽

Trisomy 8 ◽

Monosomy 7 ◽

Cell Lineages

Abstract Abstract 53 The revised 2008 WHO classification contains the newly proposed term, “refractory cytopenia of childhood (RCC)”. This term applies to children with myelodysplastic syndrome (MDS), which is characterized by a low blast count. RCC is defined as persistent cytopenia with <5% blasts in the bone marrow and <2% blasts in the peripheral blood. In addition, bone marrow aspirate smears need to show dysplastic changes in >2 cell lineages or >10% within 1 cell lineage. The distinction between RCC and aplastic anemia (AA) is normally difficult to make, especially when the bone marrow is hypoplastic and no chromosomal abnormalities can be detected. The spectrum of patients defined as having RCC is quite wide. Cases range from patients with severe hypocellular marrow and mild dysplasia in hematopoietic cells to patients with normocellular marrow and severe dysplasia that meets the criteria of refractory cytopenia with multilineage dysplasia (RCMD) in adult MDS. However, there are few studies that have focused on the difference between these two diseases. Therefore, in order to determine the specific clinical differences between AA and RCC, we retrospectively reviewed bone marrow samples of 117 bone marrow failure syndrome children (males: 69, females: 48) who were administered the same immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine. These patients were classified into AA, RCC and RCMD groups. AA patients exhibited no morphologically dysplastic changes in any of their hematopoietic cell lineages, while RCC patients had <10% dysplastic changes in >2 cell lineages, or >10% in 1 cell lineage. Patients classified as RCMD exhibited >10% of the dysplastic changes in >2 cell lineages. In accordance with the internationally defined criteria for AA, patients were further subdivided on the basis of severity, with 26 classified as non-severe, 35 as severe and 56 as very severe. At the time of initial presentation, 16 patients had a history of acute hepatitis, while one patient had the chromosomal abnormality 49,XY,+8,+16,+18. Out of the 117 patients enrolled, 58 (50%) were classified as AA, 47 (40%) as RCC and 12 (10%) as RCMD. AA and RCC patients tended to exhibit severe hypoplastic bone marrow cellularity, while the RCMD patients were normal or only exhibited mild hypoplastic marrow. The median ages in the AA, RCC, and RCMD groups were 9, 8 and 10 years, respectively. While most of the patients in the AA group (73%) had very severe disease, more than half of the RCMD patients (58%) only had non-severe disease (p<0.001). New chromosome abnormalities were detected in six patients in the AA group (monosomy 7: 4 cases, trisomy 8: 1 case, and 45,X,-X: 1 case), in one patient in the RCC group (46,XX,add(1)(q32),del(13)(q?),del(15)(q?)), and in four patients in the RCMD group (trisomy 8: 3 cases, monosomy 7: 1 case). Cumulative incidence (CI) of clonal evolution at 8 years was 10.9±4.2% in AA, 2.2±2.2% in RCC and 35.7±14.6% in RCMD (p=0.003) (Figure 1). At 6 months after IST, the response rates were 65% in AA, 70% in RCC and 58% in the RCMD group. Failure free survival (FFS) and overall survival (OS) rates at 5 years were 64.1±6.5/94.8±2.9% in AA, 60.4±7.3/97.9±2.1% in RCC and 56.3±14.8/100% in the RCMD group, respectively. A second therapeutic intervention was required in some children, with a second IST performed in eight children (3 in AA and 5 in the RCC group) and hematopoietic stem cell transplantations performed in 25 children (14 in AA, 9 in RCC and 2 in the RCMD group). Since the RCMD group exhibited a significantly high CI for clonal evolution, this suggests that the RCMD criteria should be applied to childhood MDS. However, the FFS and OS rates did not differ among these three groups. Thus, in order to definitively determine whether these three diseases are different entities, it will be necessary to use newly developed methods, such as whole exome analysis, to prospectively compare the clinical outcomes and biological findings in a larger number of the AA, RCC and RCMD patients. Disclosures: No relevant conflicts of interest to declare.

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Outcome of Standard Immunosuppressive Therapy with or without Eltrombopag for Chinese Patients with Severe Aplastic Anemia in the Real World

Blood ◽

10.1182/blood-2019-131670 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5019-5019

Author(s):

Jinsong JIA ◽

Hao Jiang ◽

Xiao Jun Huang

Keyword(s):

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Real World ◽

Antithymocyte Globulin ◽

Clonal Evolution ◽

Chinese Patients ◽

Severe Aplastic Anemia ◽

Newly Diagnosed ◽

The Real ◽

Overall Response

BACKGROUND Immunosuppression is the current standard therapy for patients with severe aplastic anemia(SAA), whereas allogeneic haematopoietic stem cell transplantation (HSCT) is recommended for patients younger than 50 years old, if donors are available. Immunosuppression with antithymocyte globulin (ATG) and ciclosporin results in an overall response rate (ORR) of about 70%. In Chinese SAA patients, porcine ATG and rabbit ATG resulted apparently in similar ORRs and survivals. The low CR rate of immunosuppression with ATG suggests that other strategies are needed to improve outcome. Eltrombopag is an oral thrombopoietin receptor agonist. In a recent study of newly diagnosed SAA patients, combined standard immunosuppressive therapy (IST) with eltrombopag, the patients in one of three cohorts who received eltrombopag from day 1 to 6 months achieved higher ORR at 6 months (94%) and CR rate(58%). The results showed a higher rate of treatment response than in the past. But the data of eltrombopag in SAA have so far been limited to clinical trials, and its efficacy in routine practice remains undefined, especially for Chinese SAA patients. Recently, we retrospectively analyzed the results of 48 cases suffer from SAA received standard immunotherapy combined with or without eltrombopag in our center, so as to explore the effects and adverse reactions in the real world. METHODS 48 consecutive newly diagnosed patients with severe aplastic anemia were enrolled in this study. Out of 48 cases, 27 were male, and 21 were female. The median age was 46 years old (ranged from 18 to 69 years old). SAA patients who received ATG combined with cyclosporine A (CsA) therapy with or without eltrombopag were analysed retrospectively. The patients were divided into a eltrombopag group (n = 14) and a without eltrombopag group (n = 34). The eltrombopag group received eltrombopag (median daily dose 75 mg) from the beginning of IST and for at least 3 months. The primary outcome was complete hematologic response at 6 months. At the same time, overall response, survival, relapse, and clonal evolution to myeloid cancer were observed. RESULTS After three months, the eltrombopag group and without eltrombopag group had an ORR of 69.5% and 47.2%, respectively (P = 0.063); after six months, the ORR reached 85.7% and 73.6%, respectively (P = 0.078). The rates of complete response at 6 months was 35.7% in the eltrombopag group and 29.4% in without eltrombopag group. The complete and overall response rates in the eltrombopag group were higher than in without eltrombopag group. However, due to the small number of cases, there was no statistical difference. At a median follow-up of 2 years, the survival rate was 97.9%; one patient died from a hematologic cause. Rates of relapse and clonal evolution were similar in two gruops. Adverse effects included reversible rashes, dyspepsia, and liver function derangement. CONCLUSIONS Rates of hematologic response among chinese patients with severe aplastic anemia treated with standard immunosuppressive therapy plus eltrombopag was markedly higher than without eltrombopag. 【Key words】 Aplastic anaemia; newly diagnosed; eltrombopag; antithymocyte globulin; Disclosures No relevant conflicts of interest to declare.

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Response to Immunosuppressive Therapy with Antithymocyte Globulin (ATG) In Older Patients with Aplastic Anemia

Blood ◽

10.1182/blood.v118.21.4374.4374 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4374-4374

Author(s):

Biju George ◽

Vikram Mathews ◽

Kavitha M Lakshmi ◽

Rayaz Ahmed ◽

Aby Abraham ◽

...

Keyword(s):

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Older Patients ◽

Antithymocyte Globulin ◽

Conflicts Of Interest ◽

Age Groups ◽

Older Age ◽

Serum Sickness ◽

Age Group ◽

Number Of Patients

Abstract Abstract 4374 Immunosuppressive therapy (IST) with antithymocyte globulin in combination with prednisolone and cyclosporine is the treatment of choice for patients with aplastic anemia who are ineligible for transplant either because of age or because of absence of a HLA identical donor. Limited data that exists on the role of immunosuppressive therapy in older patients with aplastic anemia suggest that responses were poorer. This retrospective analysis was aimed at determining whether older patients with aplastic anemia had an inferior response to IST compared with younger patients. Between October 1985 to December 2010, 322 adult patients (>12 years) were treated at our centre with antithymocyte globulin (ATG) in combination with prednisolone and with/without cyclosporine. Either ATGAM (Pharmacia Upjohn, USA) at 40 mg/kg/day × 4 days or Lymphoglobulin (Pasteur Merieux, France) at 15 mg/kg/day × 5 days was used. Prednisolone at 1 mg/kg in 3 divided doses were started one day after completion of ATG and tapered from Day +14 if there was no evidence of serum sickness. Cyclosporine at the dose of 6 mg/kg/day in 2 divided doses was started once steroids were tapered and then continued for 12 months and then tapered depending upon response. Patients were divided into 3 age groups - Ages 12 – 29 [n=116], ages 30 – 49 [n = 116] and > 50 years [n = 90]. The baseline characteristics are detailed in the table below – Thirty one patients were above the age of 60 years. The older age group had significantly higher % of males, more use of ATGAM compared with Lymphogloblin and a higher number was given Cyclosporine (CSA) post ATG. The severity of aplastic anemia (severe vs non-severe) and the median time from diagnosis to administration of ATG was not significantly different between the 3 groups. The number of patients who developed serum sickness was significantly lower in the older age group (21.1%) compared to the age group of 30 – 49 (35.3%) and 12 – 29 years (48.3%) [p = 0.000]. The overall response to ATG was similar in all 3 groups (63.8% in age 12 –29, 64.7% in ages 30 – 49 and 54.4% in age > 50 yrs) [p = 0.233]. The response in patients above the age of 60 years was 51.6%. Six patients received a second course of ATG while 3 patients underwent HLA identical sibling donor transplantation. At a median follow up of 32 months (range: 1 –145), 221 patients (68.6%) are alive. The overall survival is similar for the older age group compared with the younger age groups (66.7% with age>50 years, 68.1% with age 30–49 and 70.7% with age 12 –29) [p= 0.817]. In conclusion, immunosuppressive therapy with ATG has a reasonable outcome in older patients (> 50 years) with aplastic anemia.Table 1:Demographic characteristics and outcome of IST among the 3 age groupsVariables12 – 29 yrs (n = 116)30 – 49 yrs (n = 116)>50 yrs (n = 90)p valueMale84 (72.4%)87 (75%)52 (57.8%)Female32 (27.6%)29 (25%)38 (42.2%)0.019Severity of AA86 (74.1%)77 (66.4%)63 (70%)0.581VSAA + SAA30 (25.9%)39 (33.6%)27 (30%)NSAAType of ATG45 (38.8%)33 (28.4%)53 (58.9%)0.000ATGAM71 (61.2%)83 (71.6%)37 (41.1%)LymphoglobulinCSA used92 (79.3%)103 (88.8%)85 (94.4%)0.005Yes24 (20.7%)13 (11.2%)5 (5.6%)NoResponse74 (63.8%)75 (64.6%)49 (54.4%)0.233Overall response34 (29.3%)28 (24.1%)15 (16.7%)Complete response (CR)40 (34.5%)47 (40.5%)34 (37.8%)Partial response (PR)42 (36.2%)41 (35.3%)41 (45.6%)No response (NR)Overall survival82 (70.7%)79 (68.1%)60 (66.7%)0.817Alive34 (29.3%)37 (31.9%)30 (33.3%)Dead Disclosures: No relevant conflicts of interest to declare.

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Mutations in the Telomerase Complex and Expression Levels of the TERT Gene Determine Severity and Outcome of Disease in Aplastic Anemia Patients

Blood ◽

10.1182/blood.v128.22.1502.1502 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1502-1502 ◽

Cited By ~ 1

Author(s):

Arati Khanna-Gupta ◽

Durga Sarvepalli ◽

Snigdha Majumder ◽

Coral Karunakaran ◽

Malini Manoharan ◽

...

Keyword(s):

Aplastic Anemia ◽

Disease Severity ◽

Poor Prognosis ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Response To Therapy ◽

Hematopoietic Stem ◽

Expression Levels ◽

Shelterin Complex ◽

Tert Expression

Abstract Acquired Aplastic anemia (AA) is a bone marrow failure syndrome characterized by pancytopenia and marrow hypoplasia, and is mediated by immune destruction of hematopoietic stem cells. Mutations in several genes including telomerase, a ribonucleoprotein enzyme complex, consisting of a reverse transcriptase enzyme (TERT), an RNA template (TERC), and several stabilizing proteins, and the associated shelterin complexes have been found in both congenital and idiopathic AA. In particular, several TERT and TERC mutations reduce telomerase activity in vitro and accelerate telomere attrition in vivo. Shortened telomeres have been observed in a third of idiopathic AA patients, but only 10% of these patients have mutations in genes of the telomerase complex. We have recently demonstrated that in addition to keeping telomeres from shortening, telomerase directly regulates transcriptional programs of developmentally relevant genes (Ghosh et al, Nat Cell Biol, 2012, 14, 1270). We postulate that changes in expression of telomerase associated genes, specifically TERT, contribute to the etiology of aplastic anemia. In an effort to better understand the molecular and clinical correlates of this disease, 24 idiopathic AA patient samples were collected at a tertiary medical center in Bangalore, India. Following informed consent, we performed RT-PCR analysis on harvested RNA from each patient and measured levels of TERT expression compared to that of normal controls (n=6). An 8 fold reduction in TERT expression was observed in 17/24 patients, while 7/24 patients maintained normal TERT expression. In general, TERT-low patients were younger in age (mean age 29y) compared with the TERT-normal patients (mean age 40y). TERT-low patients were more likely to have severe aplastic anemia (SAA) leading to higher mortality and poorer response to therapy, with 6/17 patients dying and 4/17 not responding to ATG therapy. Targeted panel sequencing of the 24 samples on an Illumina platform revealed that while TERT-normal patients had no mutations in genes associated with the telomerase/shelterin complex, TERT-low patients carried predicted pathogenic variants in TERT, TEP1, TINF2, NBN, TPP1, HSP90A and POT1 genes, all associated with the telomerase complex. Somatic gene variants were also identified in other AA associated genes, PRF1 and CDAN1, in the TERT-low cohort. In addition, novel predicted pathogenic mutations associated with the shelterin complex were found in two TERT-low patients in the TNKS gene. We also detected mutations in TET2, BCORL1, FLT-3, MLP and BRAF genes in TERT-low patients. Mutations in these genes are associated with clonal evolution, disease progression and poor prognosis. Our observations were further illustrated in a single patient where normal TERT expression was noted at initial clinical presentation. ATG therapy led to CR, but the patient returned within a year and succumbed to E.coli related sepsis. At that stage he had low TERT expression, suggesting that TERT expression can change as the disease progresses. Taken together, our data support the hypothesis that loss of TERT expression correlates with disease severity and poor prognosis. Our observations further suggest that preliminary and periodic evaluation of TERT expression levels in AA patients is likely to serve as a predictor of disease severity and influence the choice of therapy. Disclosures No relevant conflicts of interest to declare.

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Paroxysmal Nocturnal Hemoglobinuria Clones Are Infrequent in Hepatitis-Associated Aplastic Anemia at the Time of Diagnosis

Blood ◽

10.1182/blood-2019-125620 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5016-5016

Author(s):

Wenrui Yang ◽

Xin Zhao ◽

Guangxin Peng ◽

Li Zhang ◽

Liping Jing ◽

...

Keyword(s):

Aplastic Anemia ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Clonal Evolution ◽

Extrinsic Factors ◽

Clone Size ◽

Hematopoietic Stem ◽

Over Time ◽

Pnh Clone

Aplastic anemia (AA) is an immune-mediated bone marrow failure, resulting in reduced number of hematopoietic stem and progenitor cells and pancytopenia. The presence of paroxysmal nocturnal hemoglobinuria (PNH) clone in AA usually suggests an immunopathogenesis in patients. However, when and how PNH clone emerge in AA is still unclear. Hepatitis associated aplastic anemia (HAAA) is a special variant of AA with a clear disease course and relatively explicit immune pathogenesis, thus serves as a good model to explore the emergence and expansion of PNH clone. To evaluate the frequency and clonal evolution of PNH clones in AA, we retrospectively analyzed the clinical data of 90 HAAA patients that were consecutively diagnosed between August 2006 and March 2018 in Blood Diseases Hospital, and we included 403 idiopathic AA (IAA) patients as control. PNH clones were detected in 8 HAAA patients (8.9%,8/90) at the time of diagnosis, compared to 18.1% (73/403) in IAA. Eight HAAA patients had PNH clone in granulocytes with a median clone size of 3.90% (1.09-12.33%), and 3 patients had PNH clone in erythrocytes (median 4.29%, range 2.99-10.8%). Only one HAAA patients (1/8, 12.5%) had a PNH clone larger than 10%, while 24 out of 73 IAA patients (32.9%) had larger PNH clones. Taken together, we observed a less frequent PNH clone with smaller clone size in HAAA patients, compared to that in IAAs. We next attempted to find out factors that associated with PNH clones. We first split patients with HAAA into two groups based on the length of disease history (≥3 mo and < 3mo). There were more patients carried PNH clone in HAAA with longer history (21.4%, 3/14) than patients with shorter history (6.6%, 5/76), in line with higher incidence of PNH clone in IAA patients who had longer disease history. Then we compared the PNH clone incidence between HAAA patients with higher absolute neutrophil counts (ANC, ≥0.2*109/L) and lower ANC (< 0.2*109/L). Interestingly, very few VSAA patients developed PNH clone (5%, 3/60), while 16.7% (5/30) of non-VSAA patients had PNH clone at diagnosis. We monitored the evolution of PNH clones after immunosuppressive therapy, and found increased incidence of PNH clone over time. The overall frequency of PNH clone in HAAA was 20.8% (15/72), which was comparable to that in IAA (27.8%, 112/403). Two thirds of those new PNH clones occurred in non-responders in HAAA. In conclusion, PNH clones are infrequent in HAAA compared to IAA at the time of diagnosis, but the overall frequency over time are comparable between the two groups of patients. In SAA/VSAA patients who are under the activated abnormal immunity, longer clinical course and relatively adequate residual hematopoietic cells serve as two important extrinsic factors for HSCs with PIGA-mutation to escape from immune attack and to expand. Disclosures No relevant conflicts of interest to declare.

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Very long-term follow-up of aplastic anemia treated with immunosuppressive therapy or allogeneic hematopoietic cell transplantation

Annals of Hematology ◽

10.1007/s00277-020-04271-4 ◽

2020 ◽

Vol 99 (11) ◽

pp. 2529-2538

Author(s):

Beatrice Drexler ◽

Felicitas Zurbriggen ◽

Tamara Diesch ◽

Romaine Viollier ◽

Joerg P. Halter ◽

...

Keyword(s):

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Hematopoietic Cell Transplantation ◽

Clonal Evolution ◽

University Hospital ◽

Term Outcome ◽

Long Term Outcome ◽

Long Term Survivors

Abstract Introduction Since the 1970s outcome of aplastic anemia (AA) patients has improved significantly due to the introduction of immunosuppressive therapy (IST) and allogeneic hematopoietic transplantation (HCT). However, patients may suffer from persistent disease, relapse, clonal evolution, graft-versus-host disease and other late effects. Here, we analyse very long-term outcome of all AA patients at our institution comparing not only survival, but also response status and complications. Methods Patient charts of all 302 AA patients treated between 1973 and 2017 at the University Hospital Basel, Switzerland, were retrospectively analysed. Results First line treatment was IST in 226 (75%) and HCT in 76 (25%) patients. Overall survival at 30 years was similar in patients treated initially by HCT and IST (44% (±14%), and 40% (± 9%) respectively, with better results in more recent years. Partial and no response occurred more frequently after IST, relapse incidence after IST was 24 %, whereas non-engraftment and graft failure was documented in 15 patients (19 %) after HCT. Clonal evolution to myelodysplastic syndrome / acute myeloid leukemia was 16 % at 25 years in IST patients, 1.3 % in HCT patients, iron overload (18 versus 4 %, p = 0.002) and cardiovascular events (11 versus 1 %, p=0.011) occured significantly more often in IST than HCT treated patients. The majority of long-term survivors, 96% of those alive at 25 years, were in complete remission at last follow up, irrespective of the initial treatment modality. Conclusion Very long term survivors after AA are those with stable hematopoietic recovery.

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Multicenter randomized study comparing cyclosporine-A alone and antithymocyte globulin with prednisone for treatment of severe aplastic anemia

Blood ◽

10.1182/blood.v79.10.2540.2540 ◽

1992 ◽

Vol 79 (10) ◽

pp. 2540-2546 ◽

Cited By ~ 5

Author(s):

E Gluckman ◽

H Esperou-Bourdeau ◽

A Baruchel ◽

M Boogaerts ◽

J Briere ◽

...

Keyword(s):

Partial Response ◽

Aplastic Anemia ◽

Antithymocyte Globulin ◽

Bone Marrow Failure ◽

Randomized Study ◽

Alternative Therapy ◽

Survival Rates ◽

Severe Aplastic Anemia ◽

Actuarial Survival ◽

Significant Difference

Abstract We report the results of a randomized multicenter study comparing the efficacy of antithymocyte globulin (ATG) with that of cyclosporin A (CsA) as first-line therapy for severe aplastic anemia (SAA). Patients were randomized to receive ATG and prednisone (PDN) or CsA; hematologic response and toxicity were compared. At 3-month evaluation, patients who had no or minimal response received the alternative therapy to assess the value of a sequential immunosuppressive therapy for treatment of severe aplastic anemia. One hundred nineteen patients were randomized; 25 were excluded, of whom 3 were misdiagnosed and 22 did not follow the cross-over protocol. Ninety-four patients were analyzed; 46 received CsA, and 48 received ATG-PDN. The actuarial survival was 66.7%, with a median follow-up time of 19 months. There was no significant difference in survival between the groups with, at 3 months, an actuarial survival of 88% in the CsA group and 75% in the ATG group (NS); at 12 months, it was 70% in the CsA group and 64% in the ATG group (NS). The percentage of complete and partial response was 11.6% and 16%, respectively, at 3 months, and 31.6% and 30%, respectively, at 12 months (NS). The main prognostic factor was the absolute neutrophil count (ANC) at entry: Patients with ANC less than 0.2 x 10(9)/L had a significantly lower survival as compared with patients with more than 0.2 x 10(9)/L ANC (P = .0001). At 12 months, 62 evaluable patients were alive, with a complete or partial response in 36 patients. Patients who had responded to the first treatment had a better recovery of bone marrow failure than those who had sequential immunosuppression. The main complication was infection, which was more often observed and more often lethal during ATG and PDN therapy. In this study, initial treatment of SAA with either CsA or ATG-PDN followed by cross-over therapy for nonresponders produced comparable response and survival rates.

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Long-Term Clinical Outcome of Patients with Acquired Aplastic Anemia In Brazil Using Cyclosporine-A (CSA) and Prednisone (PRED): 20 Years Follow-up From a Single Institution

Blood ◽

10.1182/blood.v116.21.2234.2234 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2234-2234

Author(s):

Larissa A Medeiros ◽

Samir K Nabhan ◽

Marco Antonio Bitencourt ◽

Michel M. Oliveira ◽

Vaneuza A M Funke ◽

...

Keyword(s):

Quality Of Life ◽

Overall Survival ◽

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Board Of Directors ◽

Clonal Evolution ◽

Severe Aplastic Anemia ◽

Advisory Committees

Abstract Abstract 2234 Introduction/Background: Immunosuppressive therapy is the best alternative for patients with severe aplastic anemia (SAA) without matched sibling donor or with age > 40 years. Since 1988, an alternative protocol was developed with cyclosporine (CSA) and prednisone (PRED) due to irregularity in distribution of anti-thymocyte globulin (ATG) in Brazil. This study aims to show the results of this treatment on the quality of response, overall survival and development of clonal evolution. Materials and methods: 384 patients diagnosed with SAA (Camitta and Bacigalupo criteria) were evaluable by medical records review from 12/1988 to 12/2008. The immunosuppressive therapy consisted of CSA: 12mg/kg/day BID from day (D)1- D8, then 7mg/kg/day BID until 1 year. After that CSA was progressively tapered (5% each month) and ultimately stopped usually by two years. CSA levels were kept between 200–400ng/ml. PRED: 2mg/kg/day from D1-D14 then 1mg/kg/day from D15- D45. From that day on PRED dose was tapered 20% each week. Sulfamethoxazole-trimethoprim and fluconazole were used for prophylaxis against Pneumocystis jiroveci (P carinni) and fungal diseases, respectively. Treatment response was defined as Table 1. Treatment evaluation was performed at 6 weeks, 3, 6 and 12 months and then yearly. At diagnosis: median age was 21 years (2-75), disease duration 95 days (2-4749), and median number of transfusions were 12 (0-200). Etiology was idiopathic in 78%. In peripheral blood, median hemoglobin was 7.4g/dL, granulocytes 580/uL, platelets 12.000/uL and reticulocyte 0.5% (corrected value). 60% of the patients had not been treated previously. Results: Overall survival was 61% ± 3 with a median follow-up of 7 years (range: 2 months - 23 years). Response to treatment: 51% had some degree of response, with good quality of life and transfusions independent (143 patients with complete response and 53 partial response). 36 patients had no response and there were 96 deaths. Fifty six patients have lost follow-up. Most patients achieved response between 3 and 6 months of therapy. In multivariate analysis the number of neutrophils ≥ 200/uL (p = 0.009), platelets ≥ 12.000/uL (p = 0.018), reticulocyte ≥ 0.5% (p <0.001) and starting treatment after 1997 (p = 0.002) had an impact on overall survival. Patients with 15 or more previous transfusions (p = 0.006) and age ≥ 40 years (p = 0.003) had lower survival. Overall survival was 63% ± 4 and 42% ± 6 for for patients with severe disease and very severe aplastic anemia (p <0.001). The subgroup analysis of patients under 10 years old had similar results. Among patients with response, thirty-four remained dependent of CSA. Cumulative incidence of relapse was 28% ± 4 within a median of 4.4 years. Hypertension, gingival hypertrophy and diabetes mellitus were common, but easily controlled. The rate of clonal evolution among this cohort was 7.81% (16 patients developed Paroxysmal Nocturnal Hemoglobinuria, 9 Myelodysplastic Syndrome and 5 Acute Myeloid Leukemia). Conclusion: This study, with a long follow-up, has demonstrated that the overall survival using CSA and PRED is similar to that reported with ATG therapy. Even patients with partial responses had achieved good quality of life, free from transfusions and infections. Survival was influenced by the neutrophils, platelet counts, reticulocyte, number of transfusions, age at diagnosis, and therapy started after 1997. The incidence of clonal evolution was lower when compared to reported trials with ATG + CSA. Disclosures: Oliveira: Alexion: Speakers Bureau. Funke: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pasquini: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Recombinant Human Thrombopoietin Promotes The Recovery Of Megakaryocyte Lineage In Patients With Severe Aplastic Anemia Receiving Immunosuppressive Therapy

Blood ◽

10.1182/blood.v122.21.2437.2437 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2437-2437

Author(s):

Zonghong Shao ◽

Qi'e Dong ◽

Rong Fu

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Platelet Transfusion ◽

Conflicts Of Interest ◽

Severe Aplastic Anemia ◽

Hematologic Response ◽

Patient Will ◽

Red Cell Transfusion ◽

Recombinant Human Thrombopoietin

Abstract Objective To assess the effectiveness of recombinant human thrombopoietin (rhTPO) in severe aplastic anemia (SAA) patients receiving immunosuppressive therapy (IST). Methods Eighty SAA patients receiving IST during a period from January 2007 to December 2011 were included in this retrospective analysis. Thirty-two subjects also received rhTPO treatment (15,000 U, three times a week, subcutaneously). The remaining 48 patients did not receive rhTPO treatment. The choice of using (or not using) rhTPO was based on physician discretion, and more importantly, patient will (partly based on financial capability to afford the medication). rhTPO was discontinued when platelet count returned to normal range. Hematologic response, bone marrow recovery, transfusion interval (platelet or red-cells), and the time to transfusion-free status were compared. Result At 6th months after the treatment, hematologic response along at least one lineage was achieved in 65.6% of the subjects receiving rhTPO vs. 41.7% in those who did not receive rhTPO (p=0.04). Response rate of megakaryocyte and erythroid lineage at 3rd months was also higher in subjects receiving rhTPO than in those who did not (43.8% vs. 10.4%, p=0.001; 50.0% vs. 20.8%, p=0.006). The mean number of megakaryocyte per bone marrow slide was higher in subjects receiving rhTPO than those who did not (9.7±3.1 vs. 2.6±4.2, p=0.002) after three months. The percentage of nucleated erythroid cells in bone marrow was also higher in subjects receiving rhTPO after three months (22.2±13.2% vs. 13.6±13.9% in those who did not receive rhTPO; p=0.007). The percentage of reticulocytes in peripheral blood was higher in subjects receiving rhTPO (1.9±1.4% vs. 0.7±0.4% in those who did not receive rhTPO; p=0.001) after three months. Myeloid percentage in bone marrow did not differ at any time points (3, 6, or 9 months). The need for platelet transfusion was lower in subjects receiving rhTPO (transfusion interval: 13.8±14.3 vs. 6.9±5.2 and 26.3±28.9 vs. 15.7±13.1 days in those who did not receive rhTPO during the first three and six months, respectively; P=0.004, P=0.03). The need for red cell transfusion was also lower in subjects receiving rhTPO (interval: 32.5±22.0 vs. 11.9±7.2 days and 50.4±27.9 vs. 23.9±20.1 days during the first three and six months, respectively; p=0.001 P=0.009). Time to independence from platelet transfusion was significantly shorter in subjects receiving rhTPO (99.9±49.9 vs. 156.3±14.5 days in those who did not receive rhTPO; p=0.01). Conclusion rhTPO improves hematologic response and promotes bone marrow recovery in SAA patients receiving IST. Disclosures: No relevant conflicts of interest to declare.

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