Immunosuppressive Therapy Treatment Research Articles

IST Combined with Full-Dose Rhtpo in the Treatment of Severe Aplastic Anemia -a Prospective Single-Center Clinical Study

BACKGROUND: Immunosuppressive therapy (IST) (anti-thymocyte immunoglobulin (ATG) and cyclosporine (CSA)) is the treatment of choice for patients with acquired severe aplastic anemia (SAA) who are ineligible for hematopoietic stem cell transplantation (HSCT), which results in a hematological response (HR) in about 60-70% of SAA patients, while 1/3 of patients fail to achieve a hematological response. TPO is a hepatic-secreted hematopoietic growth factor that specifically regulates platelet production, induces hematopoietic stem cell differentiation to megakaryocytes by binding to the TPO receptor (MPL), stimulates megakaryocyte proliferation and differentiation, and promotes platelet production and release. Previous retrospective studies have demonstrated that IST combined with rhTPO improves the early hematologic response in SAA patients, but efficacy reported by centers varied depending on the dose and duration of rhTPO. There are no prospective studies of rhTPO application in SAA to confirm its efficacy. So this study was designed to observe the early feeicacy and safety of the SAA patients who were treated with IST combination with full-dose rhTPO. METHODS: This study was a single-center, single-arm, prospective cohort clinical study, enrolling 33 naive SAA patients aged between 14-70 years who diagnosed after April 2021 in our study center. The patients treated with IST combined with full-dose rhTPO (300U/kg.d) for 8 weeks starting from the first day of ATG. The primary endpoint of the observational study protocol good response rate, blood product transfusion volume and safety profile at 3 months of treatment of initial SAA. The patients were also evaluated for total hematologic response rate and adverse effects of drug application, clonal shift rate, and recurrence rate at 3 and 6 months after treatment. Efficacy Criteria：Complete response (CR): HGB>100 g/L, PLT> 100×10 9/L and ANC>1.5×10 9/L; ② Good partial response (GPR): HGB>80g/L, PLT> 50×10 9/L and ANC>1.0×10 9/L; ③ Partial response (PR): withdrawal from blood product transfusion dependence (HGB>70g/L, PLT> 20×10 9/L), hematologic tests improved and no longer met the SAA criteria, but blood count did not meet the GPR criteria. ④No response to treatment (NR): Continuous transfusion dependency was classified as no response. and/or blood count still met SAA criteria. We defined CR+GPR+PR as HR and CR+GPR as good HR. RESULTS: The rhTPO group enrolled 33 patients, and the control group was 99 patients who applied the caliper value of 0.2 to match the previous unapplied TPO treatment of SAA. At 3 months after IST treatment efficacy, the HR rate of 33 patients in the rhTPO group was 66.67% (22 /33 ), and the rate of good HR was 36.4% (12/33). The HR rate in the control group was 32.32% (32 /99 ), and the rate of good HR was 12.12% (12/99). The HR rate and the good HR rate between the two group were significantly statistical differences (66.67% v 32.32%; 36.4% v 12.12%), (P value=0.001; 0.002). At 6 months after IST treatment, the HR rate and good HR rate in the rhTPO group had a significantly higher than those of the control group (66.67% v 32.32%; 36.4% v 12.12%), (P value=0.001; 0.002). No disease transformation such as myelofibrosis, myelodysplastic syndrome and acute myeloid leukemia occurred in all enrolled patients during the follow-up period. CONCLUSION: 22 of the 33 SAA patients in this study achieved HR at 3 months after IST treatment, including 36.4% cases achived good HR , which is the highest good efficacy response in a prospective study of SAA patients in China known to us to date. This confirms that full-dose rhTPO, as a macromolecular peptide, can also promote the recovery of bone marrow hematopoietic function, significantly improved the rapidity and strength of HR in SAA patients. And its clinical effect is no less than that of the various TPO-Ras that have been widely used so far, and may even be higher. 【Keywords】severe aplastic anemia; recombinant human thrombopoietin; immunosuppression treatment.

A Preliminary Report of Clinical Study on Immunosuppressive Therapy Combined with Avatrombopag As the First-Line Treatment for Severe Aplastic Anaemia in Elderly Patients

Objective The objective is to evaluate the early hematologic response (HR) rate and safety of immunosuppressive therapy (IST) combined with avatrombopag as the first-line treatment for severe/very sever aplastic anaemia(V/SAA) in elderly patients. Methods Prospective，multi-center, single-arm, clinical research. IST treatment regimen: pig anti-human lymphocyte globulin (ALG-p, Wuhan Institute of Biological Products Co., Ltd. China) 20 mg/kg/d for five days and cyclosporin A (CsA) 3 mg/kg/d with adjusted concentration of 150-250 ng/mL, and oral avatrombopag 40 mg/d from the first day of IST initiation up to six months. The patients' treatment responses were evaluated and the major adverse events were collected. Results Ten patients have been enrolled in the study at our centre from June 2022 to October 2022.Among 10 patients, six had SAA and four had VSAA; male: female = 1:1, median age of 68 (60-82) years, and median time from diagnosis to treatment of 44 (20-480) days. The patients' treatment responses were evaluated after initiation of IST, at 3 months: 7 HR [1 complete response (CR), 3 good partial response (GPR), 3 partial response (PR), and 3 no response (NR)]; and at 6 months: 8 HR (1 CR, 5 GPR, 2 PR) and 2 deaths due to infection. The median time of red-cell transfusion independence was 60 (3-168) days in HR patients and that of platelets was 60 (16-153) days. No relapse and clonal evolution occurred within six months. Major adverse events within three months were infection in five cases, electrolyte disturbance in five cases, and cardiac insufficiency in three cases. Liver function abnormalities occurred in two cases, both of which showed elevated alanine aminotransferase up to 174 μ/L and 208.7 μ/L on day 8 and 20 of IST treatment, respectively. Two of the five infected patients had sepsis caused by Enterobacter cloacae. Except for infection, the remaining adverse events were of grade I-II. All the adverse events were effectively controlled. Table 1 summarises the characteristics and clinical status of patients before and after the treatment. Conclusion This preliminary study of IST combined with avatrombopag for the treatment of elderly patients with V/SAA showed the potential of the combination to improve haematologic response rate and quality in elderly patients with AA, and it is well tolerated as well. Keywords: immunosuppressive therapy, severe aplastic anaemia, avatrombopag, elderly

Early Efficacy of IST in Combination with Hetrombopag and Rhtpo As First-Line Treatment for Naïve Severe Aplastic Anemia

BACKGROUND: Immunosuppressive therapy (IST) (anti-thymocyte immunoglobulin (ATG) and cyclosporine (CSA)) is the treatment of choice for patients with acquired severe aplastic anemia (SAA) who are ineligible for hematopoietic stem cell transplantation (HSCT), which results in a hematological response (HR) in about 60-70% of SAA patients. TPO is a hepatic-secreted hematopoietic growth factor that specifically regulates platelet production, induces hematopoietic stem cell differentiation to megakaryocytes by binding to the TPO receptor (MPL), stimulates megakaryocyte proliferation and differentiation, and promotes platelet production and release. Several previous studies have shown that IST combined with rhTPO or hetrombopag can improve the early hematologic response of SAA patients, especially the proportion of good hematologic response (good HR) in the early stage. RhTPO and TPORA have different binding sites with thrombopoietin receptor (c-MPL) and do not have competitive binding, which may produce synergistic effect. A retrospective study showed that eltrombopag combined with rhTPO increased the IST HR and improved the quality of hematologic remission in SAA with mild adverse effects. Therefore the combination of TPORA and rhTPO in SAA patients undergoing IST treatment may result in faster and higher HR rates. Clinical studies have confirmed that hetrombopag, act similarly to eltrombopag in SAA, but there are no clinical studies of hetrombopag in combination with rhTPO in SAA. OBJECTIVE: To evaluate the early-efficacy and safety profile of IST in combination with hetrombopag, and rhTPO in patients with primary, severe aplastic anemia. METHODS: This study was designed for patients with primary aplastic anemia major aged 14-70 years after January 2023 from a single center. This group were planned to be get treat of IST combination with rhTPO 15000U/d for 8 weeks from the first day of ATG and hetrombopag 15mg/d for at least 6 months. The primary endpoint was to observe the good response rate, blood product transfusion and safety profile of the study regimen for the treatment of primary SAA for 3 months. Efficacy Criteria：Complete response (CR): HGB>100 g/L, PLT> 100×10 9/L and ANC>1.5×10 9/L; ② Good partial response (GPR): HGB>80g/L, PLT> 50×10 9/L and ANC>1.0×10 9/L; ③ Partial response (PR): withdrawal from blood product transfusion dependence (HGB>70g/L, PLT> 20×10 9/L), hematologic tests improved and no longer met the SAA criteria, but blood count did not meet the GPR criteria. ④No response to treatment (NR): Continuous transfusion dependency was classified as no response. and/or blood count still met SAA criteria. We defined CR+GPR+PR as HR and CR+GPR as good HR. RESULTS: The trial group proposes to enroll 39 patients and currently includes 8 patients who can be evaluated for 3-month efficacy of IST treatment. And the control group includes two groups of IST combined rhTPO group and IST combined HPAG group in our previous center, and the cohort study of the results of the three groups. In this study, the HR rate of 8 patients can be assessed at present as 75% (6/8), and the rate of good HR was 50% (4/8). The HR of 33 patients in the control IST+rhTPO group was 66.67% (22/33), and the rate of good HR was 36.4% (12/33); the HR rate of 32 patients in the control IST+HPAG group was 46.9% (15/32), and the rate of good HR was 21.9%. The HR rate and good HR rate of the trial group were higher than those of the IST+rhTPO group and the IST+HPAG group (75%v66.67%v46.9%; 50%v36.4%v21.9%). None of the 8 patients enrolled in the trial group had any transformation of myelofibrosis, myelodysplastic syndrome and acute myeloid leukemia during the follow-up period. CONCLUSION: HR was obtained at 3 months in 6 of the 8 patients with severe remodeling IST+rhTPO+ hetrombopag in this study, with a good HR rate of 50%, which is the highest good efficacy response we know of in a prospective study of Chinese SAA patients to date. This confirms that rhTPO combined with hetrombopag can synergize the recovery of bone marrow hematopoietic function in SAA patients treated with IST, and its clinical effect is superior to that of various TPO-Ras or rhTPO that have been widely used. It is expected that more cases will be included in the later stages and that better results will be obtained. 【Keywords】severe aplastic anemia; recombinant human thrombopoietin; hetrombopag ; immunosuppression treatment.

Avatrombopag Is Effective in First-Line Treatment of Severe Aplastic Anemia: Early Outcomes of a Prospective Study

Acquired severe aplastic anemia (SAA) is a life-threatening bone marrow failure disease and its pathogenesis involves T cell-mediated autoimmunity. Antithymocyte globulin (ATG) and cyclosporine based immunosuppressive therapy (IST) is effective for patients not eligible for hematopoietic stem cell transplant, and the response rate is 60-70%. Complete hematological response (CR) predicts better survival of patients received IST treatment, but only a few patients achieve CR within 6 months (5% at 3 months and 12-17% at 6 months). Thrombopoietin receptor agonist (TPO-RA) eltrombopag improves the overall response (OR) rate and CR rate of SAA patients when combined with IST, but its hepatotoxicity is still worrying. Avatrombopag is another small-molecule TPO-RA without hepatic toxicity. We previously found that SAA patients received avatrombopag and IST as first-line treatment showed both higher CR rate and OR rate at 3 and 6 months. To validate our findings, a prospective, single-arm study of avatrombopag and IST for newly diagnosed SAA was carried out (NCT05720234). There were 25 patients enrolled in the study by June 31, 2023, including 21 SAA patients and 4 very severe aplastic anemia patients. Patients were diagnosed as AA within 6 months and received ATG, cyclosporine and avatrombopag as first-line treatment. Avatrombopag was administered at the first day of ATG initiation at dose of 60mg per day for patients weight ≥ 50kg and 40mg per day for patients weight < 50kg. ATG was given for 5 consecutive days. Cyclosporine was given orally at dose of 3.5-5mg/kg.d. There were 15 males and 10 males, at a median age of 37 years old. Eighteen patients achieved the end-point of 3 months and 10 patients achieved end-point of 6 months. There were 15 patients achieved hematologic response at 3 months (83.3%), including 5 complete responders (27.8%) and 10 partial responders. The overall response rate at 6 months was 80%, and CR rate was 60%. One patient evolved to hemolytic paroxysmal nocturnal hemoglobinuria at 3 months, with normal count of platelet and white blood cell. In conclusion, the addition of avatrombopag to IST as first-line treatment showed earlier hematologic response and higher complete response rate for patients with SAA.

Antihuman T lymphocyte porcine immunoglobulin combined with cyclosporine as first-line immunosuppressive therapy for severe aplastic anemia in China: a large single-center, 10-year retrospective study.

Antihuman T lymphocyte porcine immunoglobulin (p-ATG) has been the most common ATG preparation in immunosuppressive therapy (IST) in Chinese patients with severe aplastic anemia (SAA) since 2009. This study aimed to evaluate the early hematologic response and long-term outcomes of a large cohort of patients with SAA who received p-ATG plus cyclosporine (CsA) as first-line therapy from 2010 to 2019. This is a single-center retrospective study of medical records. We analyzed the data of 1023 consecutive patients with acquired aplastic anemia (AA) who underwent p-ATG combined with CsA as a first-line IST treatment from 2010 to 2019 at our department. The median age of the patients was 24 (4-75) years, and the median follow-up time was 57.2 months (3 days-137.5 months). There was an early mortality rate of 2.8% with a median death time of 0.9 months (3 days-2.9 months). The overall response rates were 40.6% and 56.1% at 3 and 6 months, respectively. The 5-year cumulative incidences of relapse and clonal evolution were 9.0% [95% confidence interval (CI) = 4.2-16.0%] and 4.5% (95% CI = 1.4-10.6%), respectively. The 5-year overall survival (OS) and event-free survival rates were 83.7% (95% CI = 81.1-86.0%) and 50.4% (95% CI = 47.1-53.5%), respectively. p-ATG combined with CsA for the treatment of AA is effective and safe, and p-ATG can be used as an alternative ATG preparation for the standard IST regimen in areas in which h-ATG is not available.

Patient Adherence to Immunosuppressive Therapy in Treatment of Chronic Inflammatory Eye Disease

ABSTRACT Title Patient Adherence to Immunosuppressive Therapy for Chronic Inflammatory Eye Disease Purpose To investigate adherence rates to immunosuppressive therapy (IMT) for treatment of noninfectious inflammatory eye disease (IED), adherence and disease control, and factors associated with nonadherence. Method Retrospective review of medical charts from 2015 to 2020 was conducted on patients with IED at 6 months, 1 and 2 years after initiation of IMT. Results Of 183 patients, adherence rates at 6 months and 1 year were 70% and 58% by 2 years. Eighty-two percent, 78%, and 65% of patients with disease quiescence were adherent at 6 months, 1 and 2 years, respectively. Adherent patients have 1.86 (95% CI 1.09, 3.20) times greater likelihood for disease control compared to nonadherent. Primary reason for nonadherence was patient self-discontinuation. No specific factors were associated with nonadherence. Conclusion Patients on IMT for IED had steady adherence rates up to 1 year, with decreased adherence at 2 years. Adherence to IMT significantly correlates with disease quiescence.

Whole-Exome Sequencing Identifies Fanc Heterozygous Germline Mutation As an Adverse Factor for Immunosuppressive Therapy in Chinese Aplastic Anemia Patients Aged 40 or Younger: A Single-Center Retrospective Study

Aplastic anemia (AA) is a bone marrow failure disorder characterized by pancytopenia. Currently, immunosuppressive therapy (IST) using cyclosporine (CsA) with or without anti-thymoglobulin (ATG) are the standard first-line management for AA patients not eligible for allogeneic stem cell transplantation. Several studies identified the influencing factors on IST response and survival, however, there are still a considerable number of patients suffering from poor prognosis even if they have achieved workable treatment, which encourage us to further identify additional prognosis / response predictor. The whole-exome sequencing (WES) is an accurate molecular technique to rule out congenital hematopoietic failures in young patients with pancytopenia. Up to date, several reports showed a relatively higher FANC heterozygous germline mutation rate was found in AA/MDS patients than general population, which may contribute to hematopoietic failure and confer congenital susceptibility to myeloid malignancies. Mostly, immunosuppressive therapy (IST) rescues hematopoiesis stem cell from cytotoxic T lymphocyte mediated bone marrow failure, but may exert limited effect in reconstruct gene deficit induced hematopoietic dysfunction. At present, few study focus on exploring the impact of FANC mutation on the response of AA to IST treatment, as well as its long-term prognosis. Herein, we respectively reviewed the AA patients who have the WES result in our cohort. A total of 61 patients aged ≤40 years old diagnosed with AA and underwent WES analysis were enrolled in this study, and result showed unexpected high FANC heterozygous germline mutations in our cohort (28/61, 45.9%) (Fig. A). Patients with FANC mutations have a significantly lower absolute reticulocyte count, and CD34+ % in bone marrow, and also lower 3, 6, and 9-month IST response than that without mutation, which were 0% vs. 25% (P=0.017), 26.3% vs. 42.1% (P=0.495), and 29.4% vs. 72.2% (P=0.011), especially in anti-thymocyte globulin combined with Cyclosporin A (ATG + CsA) group, which were 0% vs.33.4% (P=0.143), 25% vs.83.3% (P=0.103), and 25% vs. 100% (P=0.003), respectively (Fig. B-E). While the efficiencies of patients received HSCT were all 100% at 3rd, 6th, and 9th months evaluation. The overall survival (OS) didn't have a difference based on FANC status as well as treatment strategy (IST vs. HSCT), only one patient in the FANCmut group transformed into acute myeloid leukemia (AML) 49 months after the failure of CsA single treatment and died due to severe infection (Fig F, G). The event-free survival (EFS) in the FANCwt group was better than that in the FANCmut group (P=0.016) (Fig H), and also showed in patients received ATG + CsA treatment (P=0.045) (Fig I). We further explored the possible factors that may affect the EFS, and the FANC mutation was found to be the only predictor associated with poorer EFS [odds ratio (OR)=5.576, 95% confidence interval (CI): 1.169-26.590, P=0.031] in patients received IST (Fig J). In summary, WES based detection of FANC heterozygous germline mutations may have a great meaning in predicting IST response of acquired AA. For patients younger than 40-year-old without FANC germline mutation, ATG + CsA can exert a curative effect that was comparable to HSCT, while for cases with FANC mutation, HSCT may be a better choice. FANC germline mutation can negatively impact the IST response for Chinese patients with AA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Correlation between Serum G-CSF Level and Immune Function in Children with Aplastic Anemia

To observe the occurrence of immune dysfunction in children with aplastic anemia (AA) and the factors that may lead to immune dysfunction, analyze the relationship between the expression of granulocyte colony stimulating factor (G-CSF) and immune dysfunction. A total of 34 children with AA treated in our hospital from December 2016 to September 2018 were selected. All the children received immunosuppressive therapy (IST) for 6 months. According to whether the children had immune dysfunction after 6 months of treatment, they were divided into occurrence group and non occurrence group. General information and laboratory indices were compared between the two groups, and serum G-CSF level was tested, the relationship between serum G-CSF level and immune dysfunction in AA children after treatment with IST was observed and analyzed. After treatment with IST for 6 months, 12 cases developed immune dysfunction (35.29%). Serum interferon (IFN)-γ level of the occurrence group was higher but G-CSF level was lower than those of the non occurrence group (P<0.05), while the difference of other baseline data was not statistically significant (P>0.05). Multiple regression analysis showed that overexpression of serum IFN-γ and low expression of G-CSF were both the influencing factors of immune dysfunction in AA children after IST treatment (OR>1, P<0.05). ROC curve was drawn, and the result showed that the area under the curve (AUC) of serum G-CSF level predicted the risk of immune dysfunction after IST was 0.843>0.80, when the index cut-off value was set at 6.614 pg/ml, the predictive value was ideal. AA children have a higher risk of immune dysfunction after IST, which may be related to the low expression of serum G-CSF. The detection of serum G-CSF expression can be considered to predict the risk of immune dysfunction in AA children after IST, so as to guide early clinical intervention.

Efficacy and Safety of Hematopoietic Stem Cell Transplantation Vs. Immunosuppressive Therapy in Patients with Hepatitis-Associated Aplastic Anemia: A Single-Center Cohort Study and Meta-Analysis

Hepatitis-associated aplastic anemia (HAAA) refers to aplastic anemia (AA) in which pancytopenia appears within 6 months after an acute attack of hepatitis. The incidence of HAAA in the Far East and West accounts for 4-10% and 2-5%, respectively, in all AA cases. HAAA frequently occurs in young men, with a median age of 19 (6-56) years, and the two-month mortality after the onset of HAAA can reach 78-88% if the disease was leaved untreated. To date, the underlying pathogenesis is not yet clarified, and no specific correlation has been established between HAAA and chemical toxicants, neither radiation. Based on available studies, the hyper-activation of T lymphocytes and abnormal humoral immunity were confirmed in HAAA, and a large number of infiltrated lymphocytes are also noted in liver at the early stage of the disease, which resulting in liver dysfunction. Some viruses, including hepatitis A, hepatitis B, hepatitis C, parvovirus B19, human herpesvirus (HHV), and Epstein-Barr virus were correlated to the development of HAAA. However, the clinical results of the serological tests for hepatitis-associated viruses of most patients are negative, i.e., serologically negative HAAA.The frontline treatments are agreed to be allogeneic hematopoietic stem cell transplantation (allo-HSCT) or immunosuppressive therapy (IST). Because of the relatively scattered clinical data, compared to other acquired AA, the basis of treatment decision-making is insufficient. Some studies speculated that both IST and HSCT are effective, while others believe that transplantation should be the first choice if suitable donors are available. Therefore, we conducted a retrospective study and meta-analysis for better understanding and choice of the treatment.Our retrospective cohort study enrolled 18 HAAA patients, including 12 males and 6 females. A total of 12 (66.7%) patients received IST treatment, in which 4(33.33%) achieved completed remission (CR), 1(8.33%) partial remission (PR), and 7(58.33%) no response (NR), with a total effective rate of 41.7%. 6 patients (33.3%) received HSCT treatment, in which, 2 achieved CR, 1 PR, and 3 NR, with an effective rate of 50% (Table 1). The one-year overall survival (OS) rate of the IST group was significantly higher than that of the HSCT group (P<0.05) (Figure A). In further, we also conducted a meta-analysis which encompassed 6 studies and encompassing 345 cases. The results showed that the pooled mortality of IST and HSCT on HAAA was RR=1.16(95% CI: 0.63-2.13) (Figure B) and the difference was not statistically significant; the pooled one-year overall survival rate was RR=0.95(95% CI: 0.84-1.08)(Figure C), and the difference was not statistically significant; the pooled effective rate was RR=0.68(95% CI: 0.49-0.95)(Figure D), indicating that the efficacy of HSCT group was significantly higher than that of IST. The subgroup analysis showed that the pooled RR of the group <16-years-old was 0.61(95% CI: 0.41-0.95); the pooled RR of the group >16-years-old was 0.86 (95% CI: 0.50-1.46)(Figure E). The effective rate of ATG/ALG combined with CSA was 51.35%, and that of CSA alone was 46.7%. Compared to the HSCT group, the efficacy of ATG/ALG + CSA group (RR=0.73, 95% CI: 0.51-1.04) was better than that of CSA alone (RR=0.59, 95% CI: 0.32-1.09) (Figure F). The result of comparing ATG/ALG + CSA with CSA showed that the pooled RR was 1.35(95% CI: 0.70, 2.59) (Figure G), and the difference was not significant. This phenomenon could be attributed to the small number of articles included and insufficient sample size after subgroup analysis according to the IST treatment. We speculated that ATG/ALG combined with CSA has advantages in the treatment of HAAA compared to CSA alone.In summary, HSCT is more effective than IST in the treatment of HAAA, especially for patients <16-years-old, who should receive HSCT at the earliest. ATG/ALG combined with CSA can also be an idea option of IST treatment, but not single CsA. For patients >16-years-old, there is no significant difference in the efficacy between the HSCT and ATG/ALG + CsA strategies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Maintenance immunosuppressive therapy with resumption of immune checkpoint inhibitor treatment to reduce recurrence of immune-mediated colitis.

2642 Background: Immune-mediated colitis (IMC) may limit immune checkpoint inhibitors (ICI) treatment. Current guidelines recommend consideration of resuming ICI when IMC symptoms subside to ≤ grade 1. We aimed to investigate the effect of maintenance immunosuppressive therapy (IST) on the outcome of IMC in patients who resume ICI therapy. Methods: We retrospectively studied patients who resumed ICI therapy after adequate treatment of IMC from March 2015 to June 2020 at MD Anderson Cancer Center. Relevant demographic, oncologic, and ICI data were collected and analyzed. Univariate logistic regression analysis was conducted to assess risk factors of IMC recurrence. Results: We included 102 patients with a median age of 61 years. 66% were males and 97% were Caucasians. 48 patients (47%) received IST maintenance in conjunction with ICI resumption and 54 patients did not. Symptoms of IMC recurred in 28 patients, 8 (17%) in the concurrent IST group and 20 (37%) in the other group. Compared to no concurrent IST group, patients on concurrent IST were more likely to have received combined ICI regimen (60% vs 41%, p = 0.003) and more initial ICI doses (9 vs 5 doses, p = 0.030). Concurrent IST group had significantly longer ICI treatment duration on resumption (72 vs 62 days, p = 0.023), more ICI resumed doses (5 vs 4 doses, p = 0.038), and lower IMC recurrence (17% vs 37%, p = 0.027). Patient who received more IST doses, both therapeutic and prophylactic, had lower rate of IMC recurrence (OR 0.72, p = 0.012; table). IST maintenance treatment (OR 0.34, p = 0.024) was associated with lower IMC recurrence rate after ICI resumption. Vedolizumab was the predominant IST used. Overall survival was comparable among the two groups (p = 0.934). Conclusions: Concurrent IST treatment with ICI resumption after IMC was associated with significantly lower IMC recurrence and more extended ICI treatment while reserving similar overall survival to patients without IST maintenance therapy. Future prospective randomized trial of concurrent IST is still merited for further clarification.[Table: see text]

Long-Term Outcome Prediction After Immunosuppressive Therapy for Severe Aplastic Anemia in Childhood by Machine Learning Methods

Background: Severe Aplastic Anemia (SAA) in children is a rare severe disease, and the prognosis after immunosuppressive therapy (IST) is heterogeneous. Few models could accurately predict the long-term outcomes of immunosuppressive therapy for children SAA patients. Previous researches mainly focused on a few pretreatment factors,because SAA patients need to test the bone marrow at 3, 6, 9, and 12 months after IST treatment, and response-based surrogates of outcome have been shown to be highly predictive in other diseases. Based on these, we collected clinical electronic medical records (EMR) from 203 children with SAA, including comprehensive clinical tests from blood routine to bone marrow examination throughout the entire process, to establish a model with more effective prognostic factors to predict the prognosis of patients. Our study will provides a novel and more effective prognosis time node for reducing the times of bone marrow puncture and to guide the next treatment. Methods: Based on the machine learning methods, we established a model with the AUC 0.962 to predict the long-term outcomes in the early stage of SAA patients with IST. Findings: By analyzing the indicators related to long-term efficacy, we found that some of the indicators such as white blood cell count, lymphocyte count and absolute reticulocyte count (ARC) which are consistent with previous studies; but the age is not a suitable predictor for children with SAA, the lymphocyte ratio of bone marrow smear is more effective than lymphocyte count in blood, the C-reactive protein, level of vitamin B12, IL-6 and IL-8 in the early stage of the disease is highly correlated with long-term efficacy (P<0.05). Three months after IST can be used as a time node to guide the next treatment. Interpretation: Herein, we established a novel model regarding the prognosis analysis of children's SAA patients. We found that Third month after IST treatment can be considered as an essential time node of long-term prognosis. In addition, we further identified several new predictors (e.g. level of vitamin B12, IL-6 and IL-8, et al), but not including the factor of age. In summary, the utilization of our prediction model and identification of the effective and suitable prognostic factors are of great significance for the prognosis of children's SAA patients and the guiding of the relevant clinical treatment. Funding Statement: This work was supported by the National Key Research and Development Program of China (2016YFC0901503), the National Natural Science Foundation of China (81500156, 81170470). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: Our study has been were reviewed and approved by the Clinical Research Ethics Committee of Blood Diseases Hospital & Institute of Hematology, Chinese Academy of Medical Sciences.

Polyclonal Immune Response in T-LGL Leads to Clonal Expansions Preceding Occurrence of STAT3 Mutations Further Solidifying Clonal Dominance

T cell large granular lymphocyte leukemia (T-LGLL) characterized by excessive clonal cytotoxic T cell proliferation, is often accompanied by cytopenias and is thought to result from immune-mediated suppression, either by misguided immune antigenic recognition or mimicry triggered by auto-, tumor or viral antigens. Irrespective of the mode of evolution, T-LGLL progresses via: i) purely reactive clonal outgrowth in the context of a polyclonal immune response or: ii) a transforming event such as a STAT3 mutation (STAT3MT) within the immunodominant clone.Studies of TCR rearrangement using DNA based NGS of the TCR Vβ complementarity-determining region 3 (TCR VB CDR3) facilitate analyses of T cell clonality, as the CDR3-based “biological barcodes” allow for clonal quantification. We used serial CDR3 clonotyping accompanied by clonal STAT3 mutant burden measurements to recapitulate the pathological cascade in the course of T-LGLL. We asked if a polyclonal/oligoclonal immune response is the primary process that is clonally “imprinted” by STAT3MT, which would likely arise with the most proliferative clone. We were interested in the dynamics of underlying clonal behavior during treatment.Our initial cohort included 207 well characterized LGL patients. Most presented with anemia (46%), and/or neutropenia (46%). VB expansion was present in 94% of cases, with an average LGL count of 2317k/uL .STAT3MT were found by targeted deep sequencing in 38% of patients in 4 common hotspots: 42% Y640F, 34% D661Y, 11% D661V, and 8% N647I, with an average clonal burden of 28%. Multiple STAT3MT variants were found in some patients. From this cohort, serial samples obtained at presentation and throughout clinical course were obtained from 20 representative cases (10 STAT3MT and 10 STAT3WT), and subjected to analysis of clonal dynamics, including simultaneous deep TCR VB and STAT3 NGS. Patients were sequenced at an average of 4 time points (range 2-8). At least one major clonotype was identified in all patients, and multiple major clonotypes were identified in half.Analyses of clonal architecture revealed that STAT3 clones arose with VB expanded clones. In all cases, the TCR clonal burden was greater than that of STAT3MT demonstrating for the first time that STAT3MT is not the ancestral event for clonal expansion; rather, it evolves within the pre-expanded immunodominant clone.More than half of the patients were treated with immunosuppressive therapy (IST) achieving an approximate 40% response rate. Distinct patterns of clonal dynamics were seen following treatment (see Figure). In some patients, both the STAT3 (if present) and the major TCR clone decreased upon successful therapy. A correlation between a specific IST treatment and a clonal burden decrease was not found. In a subset of patients, the clones persisted despite a hematologic response, suggesting the major clonotype was functionally silenced. We also observed a common phenomenon of TCR “clonotype switching”, whereby therapy contracts one major clonotype, while another previously “minor” clonotype emerges. These newly expanded clones did not harbor STAT3MT, and most patients with “switching” were resistant to IST therapy. Multiple clonotypes were present at initial sampling in a few patients without STAT3MT and persisted at the same rate in subsequent samplings, precluding identification of a clear immunodominant clonotype. A stable or increasing clonal burden of both STAT3MT and VB CDR3 was seen in IST non-responders.In sum, STAT3MT were found to be a secondary event to the clonal expansion of the TCR VB clonotype, as a response within an already expanded clonotype and not the initiator of clonal expansion. The dynamics of both the STAT3MT and the TCR VB clonotype can be assessed over disease course and treatment regimens and demonstrate additional clinical ultility when applied to larger prospective clinical trials. The difficulty in finding a direct correlation between response to specific IST and a decrease in TCR VB clonal burden may be due to variable time frames between samplings, heterogeneity of IST regimens and response assessment, or large asymptomatic clonotypes. Prior to this study, the association of remission and elimination of immunodominant clonotypes was unclear. Our results suggest that clonal elimination is not necessary for complete clinical response; rather, the clone can be contracted to a manageable clonal burden or silenced. DisclosuresMustjoki:Novartis: Honoraria, Research Funding; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy.

Effects and Predictive Factors of Immunosuppressive Therapy Combined with Umbilical Cord Blood Infusion in Patients with Severe Aplastic Anemia.

PurposeTo investigate the efficacy and safety of umbilical cord blood (UCB) infusion (UCBI) plus immunosuppressive therapy (IST) treatment in comparison to IST treatment, as well as predictive factors for clinical responses, in severe aplastic anemia (SAA) patients.Materials and MethodsTotally, 93 patients with SAA were enrolled in this cohort study. In the IST group, rabbit antithymocyte globulin (r-ATG) combined with cyclosporine A (CsA) was administered, while in the IST+UBCI group, r-ATG, CsA, and UCB were used.ResultsAfter 6 months of treatment, UCBI+IST achieved a higher complete response (CR) rate (p=0.002) and an elevated overall response rate (ORR) (p=0.004), compared to IST. Regarding hematopoietic recovery at month 6, platelet responses in the UCBI+IST group were better than those in the IST group (p=0.002), and UCBI+IST treatment facilitated increasing trends in absolute neutrophil count (ANC) response (p=0.056). Kaplan-Meier curves illuminated UCBI+IST achieved faster ANC response (p<0.001) and platelet response (p<0.001), compared with IST therapy. There was no difference in overall survival (OS) between the two groups (p=0.620). Furthermore, logistic regression analysis demonstrated that UCBI+IST was an independent predicting factor for both CR (p=0.001) and ORR (p<0.001), compared to IST; meanwhile, very severe aplastic anemia (VSAA) and ANC could predict clinical responses as well. However, Cox proportional hazard regression indicated that VSAA (p=0.003), but not UCBI+IST, affected OS. Safety profiles showed that UCBI+IST therapy did not elevate adverse events, compared with IST treatment.ConclusionUCBI+IST achieved better clinical responses and hematopoietic recovery than IST, and was well tolerated in SAA patients.

Evaluation of efficacy of immunosuppressive therapy plus recombinant human thrombopoietin for children with severe aplastic anemia

Objective: To evaluate the therapeutic efficacy and safety of immunosuppressive therapy (IST) combined with recombinant human thrombopoietin (rhTPO) for severe aplastic anemia (SAA) in pediatric patients. Method: A retrospective case-control study was conducted and the clinical data of 45 pediatric patients with de novo SAA admitted to the Anemia Diagnosis and Treatment Center of Chinese Academy of Medical Sciences & Blood Disease Hospital during the period from December 2009 to December 2014 were analyzed. Among them, 15 patients were treated with the regimen of IST together with rhTPO and 30 patients were given IST treatment only. The variation characteristics of the peripheral blood routine as well as the transfusion of blood products was dynamically observed, and the therapeutic efficacy was assessed respectively after 3, 6 and 12 months after the treatment. In the meantime, adverse effects related to rhTPO application were recorded. Thereafter, the statistics of the two groups were compared by non-parametric rank sum test. Result: Among 45 pediatric patients, there were 26 male and 19 female, and the median age was 11 years (6-14). The number of patients received good hematological response(complete remission (CR) plus good partial response (GPR)) in the combinatory group versus vs. the IST group was 6 vs. 3 patients (χ(2)=3.906, P=0.048) at the 3rd month, 7 vs. 7 patients (χ(2)=1.568, P=0.210) at the 6th month, and 13 vs. 14 patients (χ(2)=6.667, P=0.01) at the 12th month respectively. For those achieved good hematological response at the 3rd month, the amount of platelets transfusion and red blood cells transfusion of the combined group were both less than that of the IST group during the period from the 10th to the 12th weeks (platelets transfusion: 1.4 U vs. 2.9 U, t=-3.523, P=0.002; red blood cells transfusion: 0.8 U vs. 2.6 U, t=-2.392, P=0.026). No serious adverse effect related to rhTPO application was observed in the IST combined with rhTPO group. Conclusion: Application of rhTPO can improve the short-term therapeutic efficacy of IST for pediatric SAA, alleviate transfusion dependence, and has a good safety profile.

A study of immunocyte subsets and serum cytokine profiles before and after immunal suppression treatment in patients with immune thrombocytopenia

To explore the clinical significance of a series of cytokines and peripheral blood immunocyte subsets before and after immunosuppressive therapy in patients with immune thrombocytopenia (ITP). The percentages of immunocyte subsets in the peripheral blood of 20 patients with ITP and 20 healthy controls were detected by flow cytometry, including CD3(+), CD4(+), CD8(+), CD4(+)/CD8(+), CD19(+). ELISA was applied to detect the level of serum TNFα, IL-2, IL-6, IL-4, IL-10, IL-11, IL-17, IL-27, transforming growth factor β (TGFβ), thrombopoietin (TPO) of 20 patients with ITP and 20 healthy controls. The percentage of CD3(+) T lymphocyte, CD4(+) T lymphocyte and the ratio of CD4(+)/CD8(+) T lymphocyte in patients with ITP were lower than those in healthy controls[(62.66 ± 6.58)% vs (69.93 ± 4.81)%, (29.46 ± 5.02)% vs (39.08 ± 3.50)%, 0.97 ± 0.35 vs 1.56 ± 0.26, all P<0.05]. After immunosuppressive therapy, the percentage of CD3(+) T lymphocyte, CD4(+) T lymphocyte and the ratio of CD4(+)/CD8(+) T lymphocyte [(71.49 ± 5.16)%, (39.25 ± 3.21)% and 1.56 ± 0.28] recovered to the same levels in healthy controls. The percentage of CD8(+) T lymphocyte and CD19(+) B lymphocyte in patients with ITP were higher than those in the healthy controls [(30.28 ± 4.63)% vs (25.90 ± 3.06)%, (18.92 ± 4.27)% vs (13.17 ± 3.64)%, all P<0.05]. After treatment of immunosuppressive therapy, the percentage of CD8(+) T lymphocyte and CD19(+) B lymphocyte [(25.16 ± 3.45)% and (11.98 ± 3.68)%] recovered to the similar levels in healthy controls. The serum levels of IL-4, IL-6, IL-11, IL-17 and TPO in patients with ITP were significantly higher than those in healthy controls. While TGFβ level was significantly decreased. There was no significant difference of IL-27 between ITP patients and healthy controls. After the treatment of immunosuppressive therapy, IL-4, IL-6, IL-11, IL-17, TPO and TGFβ were down-regulated while IL-27 was up-regulated. There was no significant difference of IFNγ, TNFα, IL-2 and IL-10 among ITP patients before or after immunosuppressive therapy and healthy controls. The present study suggests that the aberrant immunocyte subsets and cytokines are involved in the pathogenesis of ITP. Hyper-function of Th2 and Th17, dysfunction of Treg cells, up-regulation of IL-27, IL-11, TPO and other factors may contribute to the pathogenesis of ITP.

Interim Results of a Multi-Center Observational Study of Current Treatment Patterns for Patients with Severe Aplastic Anemia (SAA), Very Severe Aplastic Anemia (VSAA) and Transfusion-Dependent Non-Severe Aplastic Anemia (TD-NSAA) in China

BackgroundIn China, the incidence of aplastic anemia (AA) is about 0.74/105, with 0.14/105 of severe aplastic anemia (SAA). Most of these SAA patients are treated in big medical centers or traditional Chinese medicine (TCM) hospitals, which could stand for the current practices in China. Despite the China Aplastic Anemia Consensus, published in 2010, recommended that the immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT) were the standard treatment for SAA, very severe aplastic anemia (VSAA) and transfusion-dependent non-severe aplastic anemia (TD-NSAA), the current treatment options for patients with these diseases are diverse, including antithymocyte globulin (ATG)/antilymphocyte globulin (ALG) + cyclosporin A (CsA), CSA + androgen, CSA or androgen alone, only supportive care, TCM, etc. This national disease registry study aimed to describe the current clinical practice and treatment patterns for SAA, VSAA and TD-NSAA patients in China and understand their IST patterns as well as the supportive care measures.MethodsIn this prospective, multi-center, observational study, adult or pediatric patients diagnosed as acquired aplastic anemia within 3 months and met the guideline criteria of SAA, VSAA or TD-NSAA were enrolled from October 2012 to April 2014. All enrolled patients will be followed at least for one year. Each subject will be visited every 3 months in the first year and every 6 months from the second year until the patients withdraw the ICF or study close. The main evaluation criteria is the treatment patterns of SAA, VSAA and TD-NSAA which will be specified as: IST (ATG + CsA, CsA + androgen, CsA and others), HSCT, TCM, androgen, supportive care and others. The response of SAA/VSAA and TD-NSAA after each treatment, and serious adverse events, will also be evaluated by the investigators. An interim analysis is planned when all patients have been enrolled (target N=350) and will focus on their baseline characteristics and first treatment choice. This study was sponsored by Sanofi.ResultsA total of 352 patients were enrolled at 29 sites in China (SAA 221 pts; VSAA 84 pts; TD-NSAA 47 pts). The median age was 21 years (range, 0-84) and 65.1% were adults. 51.7% were male and 71.6% had ECOG PS <2. The vast majority of enrolled patients (344/352 pts, 97.7%) had no previous AA-related history. The most common onset symptom at baseline was anemia (92.9%), followed by hemorrhage (72.2%), infection (56.8%) and others (3.4%). TD-NSAA patients had less infections than SAA or VSAA patients (25.5% vs. 57.9%/71.4%). Cytogenetic abnormality were detected in 6.1% of the 245 patients who received cytogenetic test at baseline. The analysis of the primary endpoint showed 74.1% and 4.3% of the total patients received IST and HSCT at baseline, respectively. Among the patients with IST treatment, the standard ATG + CsA treatment was only applied in 26.4% of them (SAA 25.5%; VSAA 42.4%; TD-NSAA 5.4%). The other IST regimens were CsA + androgen (31.0%), CsA (31.4%) and others (11.1%). Three different brands of ATG/ALG were used in patients with IST: Rabbit ATG (75.0%), ATG-Fresenius (2.1%) and ALG-Porcine (22.9%). TCM therapy were applied in 12.8% of the total patients and were more common in SAA/VSAA patients (15.8% & 10.7%, respectively) than in TD-NSAA patients (2.1%). 2.8% of the patients received androgen therapy alone at baseline. 8 patients (2.3%) had switched their treatment pattern within 3 months before the enrolment because of unsatisfying efficacy (5 pts) or personal reasons (3 pts). Supportive care was applied in 95.7% of the total patients. The supportive care measures included blood transfusion (97.9%), antibiotics (64.1%), hematopoietic growth factors (58.8%), protective isolation (46.6%), iron chelators (0.3%) and others (2.7%). When the study initiated, the first treatment choice for all patients were IST (74.1%), HSCT (3.4%) and others (22.4%). There were no substantial difference of the first treatment pattern among SAA, VSAA and TD-NSAA groups.ConclusionsChinese AA patients received diverse treatments in real life clinical practice. Based on this interim analysis, 74.1% of the SAA, VSAA and TD-NSAA patients in China received IST. But only 26.4% of them received the standard ATG + CsA therapy. TCM therapy still played a role in the treatment, especially for SAA and VSAA patients in China. Final results including efficacy and safety profiles will be reported later. DisclosuresOff Label Use: Anti-thymocyte globulin-Fresenius is used as an immunosuppressive therapy for the treatment of aplastic anemia.

Comparison of rabbit antithymocyte globulin and Jurkat cell-reactive anti-t lymphocyte globulin as a first-line treatment for children with aplastic anemia

The purpose of this study was to investigate the effects of rabbit antihuman thymocyte globulin (R-ATG) and Jurkat cell-reactive anti-T lymphocyte globulin (ATG-F) in the treatment of childhood aplastic anemia (AA) and compare their efficacy and side effects. A total of 53 children with AA were analyzed in the present study, including 32 cases of severe AA, 10 cases of very severe AA and 11 cases of transfusion-dependent nonsevere AA. While receiving immunosuppressive therapy (IST), 29 and 24 patients, all of whom received long-term oral supplement with cyclosporin A (CSA), androgen, and traditional Chinese medicines, were treated with R-ATG and ATG-F, respectively. If necessary, the patients were also given supportive care such as component transfusion and/or infection control. Absolute counts of peripheral blood lymphocyte at various time points were dynamically measured after ATG therapy. According to the International AA Treatment and Effect standards, we found that there were no statistically significant differences in the response rate (70.83% vs. 68.97%, p > 0.05) and the overall survive rate (83.33% vs. 82.76%, p > 0.05) between the ATG-F and R-ATG groups. In addition, no obvious differences were observed between these two groups in the response time, efficacy in severe AA and very severe AA, or the incidence rates of ATG-related adverse reactions. After ATG treatment, the extent of peripheral blood lymphocyte reduction and duration in peripheral blood were similar between the ATG-F and R-ATG groups. The results of this study showed that ATG-F and R-ATG had similar efficacy and adverse reactions in the first-line treatment of childhood AA, despite being derived from different immunogens.

New therapeutic approaches for protecting hematopoietic stem cells in aplastic anemia

Aplastic anemia (AA) is an immune-mediated and life-threatening form of acquired bone marrow failure (BMF), characterized by development and expansion of self-reactive T cells. These T cells cause continuous destruction of hematopoietic stem cells (HSCs), progenitors, and mature blood cells, leading to severe and if left untreated fatal marrow hypoplasia and pancytopenia. Standard treatment options for patients with AA include: (1) immunosuppressive therapy (IST) with anti-thymocyte globulin and cyclosporine A which targets self-reactive T cells, or (2) matched sibling or unrelated BM transplant (BMT). The IST treatment is often not effective due to poor response to therapy or disease relapse after IST. Also, BMT is not an option for many patients due to their age, comorbidities, and the lack of histocompatible donor. This necessitates development and testing of novel approaches to reduce severity of AA and to efficiently treat patients with refractory and relapsed AA. Immune-mediated AA was reproduced in animals, including mouse lymphocyte infusion models, which are used to study further etiology and pathophysiology of AA and test new drugs and approaches in treating and managing AA. In these mouse models the immune correlates and pathologic features of AA are strikingly similar to features of severe human AA. In this article we (a) briefly review standard and developing approaches for treating AA and (b) describe development and testing of novel treatment approach with a potential to safely reduce BM hypoplasia and significantly decrease the loss of HSCs in mouse lymphocyte infusion model of AA.

Pulmonary hypertension in rheumatic diseases: epidemiology and pathogenesis

The focus of this review is to increase awareness of pulmonary arterial hypertension (PAH) in patients with rheumatic diseases. Epidemiology and pathogenesis of PAH in rheumatic diseases is reviewed, with recommendations for early screening and diagnosis and suggestion of possible role of immunosuppressive therapy in treatment for PAH in rheumatic diseases. A MEDLINE search for articles published between January 1970 and June 2012 was conducted using the following keywords: pulmonary hypertension, scleroderma, systemic sclerosis, pulmonary arterial hypertension, connective tissues disease, systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis, Sjogren's syndrome, vasculitis, sarcoidosis, inflammatory myopathies, dermatomyositis, ankylosing spondylitis, spondyloarthropathies, diagnosis and treatment. Pathogenesis and disease burden of PAH in rheumatic diseases was highlighted, with emphasis on early consideration and workup of PAH. Screening recommendations and treatment were touched upon. PAH is most commonly seen in systemic sclerosis and may be seen in isolation or in association with interstitial lung disease. Several pathophysiologic processes have been identified including an obliterative vasculopathy, veno-occlusive disease, formation of microthrombi and pulmonary fibrosis. PAH in systemic lupus erythematosus is associated with higher prevalence of antiphospholipid and anticardiolipin antibodies and the presence of Raynaud's phenomenon. Endothelial proliferation with vascular remodeling, abnormal coagulation with thrombus formation and immune-mediated vasculopathy are the postulated mechanisms. Improvement with immunosuppressive medications has been reported. Pulmonary fibrosis, extrinsic compression of pulmonary arteries and granulomatous vasculitis have been reported in patients with sarcoidosis. Intimal and medial hyperplasia with luminal narrowing has been observed in Sjogren's syndrome, mixed connective tissue disease and inflammatory myopathies. Pulmonary arterial hypertension (PAH) associated with rheumatic diseases carries a particularly grim prognosis with faster progression of disease and poor response to therapy. Though largely associated with systemic sclerosis, it is being increasingly recognized in other rheumatic diseases. An underlying inflammatory component may explain the poor response to therapy in patients with rheumatic diseases and is a rationale for consideration of immunosuppressive therapy in conjunction with vasodilator therapy in treatment for PAH. Further studies identifying pathogenetic pathways and possible targets of therapy, especially the role of immunomodulatory medications, are warranted.

Effects of Eculizumab Therapy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Receiving Concurrent Immunosuppressive Therapy for Bone Marrow Insufficiency.

Abstract 3012Poster Board II-988PNH is a progressively debilitating and life-threatening disease characterized by chronic complement-mediated hemolysis. PNH evolves from a somatic mutation of the PIG-A gene in hematopoietic stem cells that leads to the loss of the GPI-anchored complement inhibitor proteins CD55 and CD59 on the surface of blood cells. The loss of complement inhibitors leads to complement-mediated hemolysis that underlies the life-threatening thrombosis, chronic kidney disease, pulmonary hypertension, and organ damage, as well as significant morbidities including impaired quality of life and anemia in PNH. PNH cells can be found in up to 70% of patients with aplastic anemia (AA), a bone marrow failure (BMF) syndrome, suggesting a common immune-mediated pathophysiology for the initial evolution of both PNH and AA. However, each disease is associated with different morbidities and mortality that requires distinct treatments. The aplasia of AA may be effectively treated with immunosuppressive therapy (IST). The unregulated terminal complement activation and hemolysis associated with PNH can be effectively treated with eculizumab, a humanized anti-C5 monoclonal antibody that inhibits terminal complement activation. We conducted a post hoc review of the PNH clinical trial database (N=195) to evaluate the efficacy and safety of eculizumab in a population of patients (n=17) receiving concomitant IST. In the first group, 12 patients (11 with AA; 1 pancytopenic) were started on cyclosporine A (CSA) from 9.8 to 160 months before eculizumab treatment. Patients were treated with CSA and concomitant eculizumab for a median of 2.5 years (8 patients maintained IST throughout the entire clinical program; 4 patients stopped IST). The median PNH granulocyte clone size was 88%. At baseline, despite IST, there was on-going hemolysis as measured by elevated LDH (median, 1,150 U/L), patients were severely fatigued (median FACIT-fatigue 22.8) and had substantial transfusion use (median 10 U/year per patient). The addition of eculizumab therapy significantly reduced hemolysis (P=0.002, 0.003, and 0.002 vs baseline, at 3, 6 and 12 months, respectively) and significantly improved fatigue (P=0.033, 0.042, and 0.024 vs baseline at 3, 6 and 12 months, respectively) in patients concomitantly treated with IST. Fatigue improved with eculizumab treatment without significant hemoglobin change and prior to a reduction in transfusion requirements (P=0.036 and 0.019 vs baseline at 6 and 12 months, respectively). In the second group, 5 patients started on IST treatment while already undergoing treatment with eculizumab. Patient medical history included 2 patients with pre-existing AA, 1 with pre-existing thrombocytopenia and 2 with no recorded pre-existing cytopenia. The median granulocyte clone size was 92 %. At the individual principal investigator's discretion, IST was started 1 to 19 months after the start of eculizumab.IST regimens included CSA alone (1), CSA/Azathioprine (1), CSA/ALG (1), CSA/ATG (1), or CSA/alemtuzmab (1). At the time of the first dose of IST, absolute neutrophil count (ANC) ranged from 0.9 to 1.1×109/L, platelet counts ranged from16 to 165 ×109/L and reticulocyte counts ranged from 1.9 to 7.5. Three of the five (60%) patients demonstrated a partial response to IST treatment added to eculizumab (Patient 1: Hgb increased +3.4 g/dL; Patient 2: platelet count increased >2 fold, transfusion independent; Patient 3: ANC increased >2 fold, transfusion independent). In both patient groups, the overall and infection-related adverse event rates and serious event rates (calculated as # events / patient / month) were similar to the overall clinical trial population and did not increase over time. In summary, PNH may be associated with some degree of bone marrow failure (frequently from mild cytopenia to severe AA). We show that patients with BMF and PNH treated with IST alone can continue to experience hemolysis, contributing to patient morbidities due to PNH. Patients with hemolysis who are already on IST can be given eculizumab, reducing hemolysis and subsequent morbidities. While eculizumab is approved to treat PNH patients with hemolysis it is not expected to affect the aplastic bone marrow component. A proportion of the patients who develop worsening cytopenias on eculizumab will respond to IST. Finally, we demonstrate that eculizumab appears well tolerated in patients requiring IST for their marrow failure. [Display omitted] Disclosures:Schrezenmeier:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schubert:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Muus:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Socie:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Risitano:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Alexion: Honoraria. Hillmen:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.