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Objective: To study the metabolic characteristics of anti-human T-cell porcine immunoglobulin (p-ATG) in patients with severe aplastic anemia (SAA) . Methods: For patients with SAA treated with p-ATG combined cyclosporine A (CsA) immunosuppressants between February 2017 and December 2017, the p-ATG dose was 20 mg·kg(-1)·d(-1) over 12 h of intravenous administration for 5 consecutive days. The blood concentration of p-ATG was detected by the three-antibody sandwich ELISA method, the pharmacokinetic analysis software was fitted, and the second-chamber model method was used to calculate the pharmacokinetic parameters and plot the pharmacokinetic curve. Adverse events were recorded and the hematologic reactions were determined at 6 months after treatment. Results: Sixteen patients with SAA treated with p-ATG were enrolled, including 8 females and 8 males, with a median age of 22 years (range, 12 to 49 years) and a median weight of 62.5 kg (range, 37.5 to 82.0 kg) . The pharmacokinetics of p-ATG could be evaluated in 14 cases. p-ATG is distributed in vivo as a two-chamber model, with an average drug concentration peak (T(max)) of (5.786±2.486) days, a peak concentration (C(max)) of (616±452) mg/L, and a half-life of (10.479±8.242) days. The area under the drug time curve (AUC) was (5.807±3.236) mg/L·d. Six months after treatment, 8 of 14 patients received a hematologic response; the AUC (0-t) of the effective group and ineffective groups was (7.50±3.26) mg/L·d vs (4.50±2.18) mg/L·d, and the C(max) was (627±476) mg/L vs (584±382) mg/L, respectively. Conclusion: The plasma concentration of p-ATG reached a peak after 5 days of continuous infusion, and then decreased slowly, with a half-life of 10.479 days, and the residual drug concentration was detected in the body 60 days after administration. A relationship between drug metabolism and efficacy and adverse reactions could not be determined.

Objective: To analyze the prognostic factors of transfusion-dependent non-severe aplastic anemia (TD-NSAA) patients treated with cyclosporine A (CsA) and androgen. Methods: Clinical data of 77 consecutive TD-NSAA patients treated with CsA and androgen were retrospectively analyzed between 2010 and 2013. We obtained clinical manifestations and baseline parameters of routine blood test from responders, and compared those with non-responders. All data were analyzed by univariate analysis and multivariate analysis. Results: In 77 patients, there were 43 (55.8%) patients achieved hematological response after 6 months'treatment, and 53 (68.8%) patients got response after 12 months. Univariate analysis showed that platelets baseline was the only factor related to hematological response [19 (6-61) ×10(9)/L vs 13.5 (5-45) ×10(9)/L, P =0.001] after 6 months therapy. After 12 months, the statistical differences were maintained, which were platelets baseline [18 (6-61) ×10(9)/L vs 10.5 (5-45) ×10(9)/L, P <0.001], absolute reticulocytes [0.03 (0.01-0.06) ×10(12)/L vs 0.029 (0.02-0.06) ×10(12)/L, P =0.043], transfusion-dependent of platelet ( P =0.007) , transfusion-dependent of platelet and erythrocyte ( P =0.012) . Multivariate analysis showed that platelets baseline could be an independent prognostic factor of hematological response ( P =0.010 or 0.009) . Cutoff value of platelets by receiver operating characteristic curve was 15.5×10(9)/L. Conclusion: Baseline of higher platelets, higher reticulocyte, and no transfusion dependence of platelet are favorable prognostic factors. When platelets baseline is higher than 15.5×10(9)/L, CsA and androgen regimen is rational.

Objective: To explore the life span of red blood cells (RBC) in patients with severe/very severe aplastic anemia (SAA/VSAA). Methods: Clinical data of 128 SAA/VSAA patients from November 2016 to April 2017 were retrospectively analyzed, and 13 healthy volunteers in the same period was used as normal control. The endogenous Breath Carbon Monoxide (CO) test was used to detect the life span of RBC in SAA/VSAA patients, and the effect of immunosuppressive therapy (IST) on the life span of RBC in these patients was explored. Results: The mean life span of RBC in 51 untreated SAA/VSAA patients was (50.69±21.43) d, which was significantly shorter than that in normal controls[(111.85±31.55) d]( t =-6.611, P <0.001). The mean life span of RBC in 77 patients treated with IST was (87.14±39.28) d. The mean life span of RBC in complete responses (CR), hematologic response (HR) and non-response (NR) patients were (106.15±32.12) d, (92.00±38.60) d and (50.44±21.56) d, respectively. The life span of RBC in patients with HR was significantly longer than that in newly diagnosed and NR patients ( t =7.430, P <0.001; t =4.846, P =0.002), which was similar to that in the normal controls ( t =-1.743, P =0.085). There was no statistical significance between CR patients and the normal controls in the mean life span of RBC ( t =-0.558, P =0.579). No factor affecting the RBC life span was found in univariate logistical regression analyses in the newly diagnosed SAA/VSAA patients. The serum levels of IL-2R and IL-6 were much lower in HR patients than NR patients[IL-2R: 4.3×10 5 U/L vs 6.5×10 5 U/L, z =-2.733, P =0.006; IL-6: 2.6 (2.0-17.7) ng/L vs 6.1 (2.0-14.4) ng/L, z =-2.968, P =0.003]. Of the 51 newly diagnosed patients, 38 received IST and their 3-month curative effect was evaluated. Receiver operator characteristics (ROC) curve was used to analyze the predictive effect of RBC life span of untreated patients on the efficacy of IST before treatment. The cut-off point was 60 days with sensitivity of 37.5% and specificity of 86.4%. In 9 cases with life span of RBC>60 d before IST, 6 cases acquired HR, while in 29 cases with life span of RBC ≤ 60 d before IST, 10 cases acquired HR, the difference was not statistically significant ( P =0.128). Conclusion: The life span of RBC in SAA/VSAA patients was shortened, which can be improved even recovered to the normal after IST. Elevated cytokines might play a role in the pathophysiology of the shortened RBC life span in SAA/VSAA.

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.

Objective: To explore the characteristics of delayed hematologic response in very/severe aplastic anemia (V/SAA) patients who were treated with immunosuppressive treatment (IST) as first-line approach, and investigate the rationality of early salvage treatment in refractory patients. Methods: The data of V/SAA patients front-line treated with IST were retrospectively analyzed. Delayed response was defined as acquiring hematologic response between 6 and 12 months after 1 course of IST. The clinical as well as hematologic characteristics of the delayed responded patients were investigated. Results: Of the 533 patients, 45 (8.44%, 45/533) were delayed hematologic responders, which accounted for 29.03% (45/155) of the whole non-responders at 6 months. The quality of response in delayed responders analyzed at 12 months (χ 2 =62.616, P <0.001) and at the end of follow-up (χ 2 =6.299, P =0.043) was significantly worse than that of robust response group. There were more VSAA patients in delayed response group compared with robust response group (57.8% vs 38.3%, P =0.013), and all the baseline absolute reticulocyte (ARC) count, ARC proportion and absolute neutrophil count (ANC) were much lower than that in delayed response group. Multivariate analysis about the above 2 groups showed that the baseline ARC count <10×10 9 /L significanty reduced the chance of hematologic response within 6 months [ OR =3.641(95% CI 1.718-7.719) , P =0.001], and not any factor was found to predict delayed hematologic response in non-responders at 6 months. The 5-year overall survival of 76.50% (95% CI 71.6%-81.4%) and event free survival of 29.10%(95% CI 25.2%-33.0% ) in non-responders at 6 months, both were worse than 97.6% (95% CI 96.6%-98.6% ) and 84.0% (95% CI 81.1%-86.9% ) ( P <0.001) of robust response group. Conclusion: The incidence of delayed hematologic response in V/SAA patients by IST is low. The quality of delayed response is not satisfactory and there is no effective means to predict the delayed response. It is reasonable to carry out salvage treatment as early as possible.

Objective: To determine whether cyclosporine A (CsA) plus androgens was as effective as the current standard immunosuppressive therapy (IST) for transfusion-dependent nonsevere aplastic anemia (TD-NSAA). Methods: The records of 125 consecutive TD-NSAA patients who were treated between Aug. 2007 and Sept. 2014, with either CsA plus androgen or ALG/ATG plus CsA regimen were reviewed. The 3-month and 6-month hematologic responses and survival were evaluated. Results: There were 125 TD-NSAA patients (70 were male and 55 female, 1.25∶1). Median age was 27 (6-66) years. There was no significant difference in early mortality between 48 treated by ATG/ALG plus CsA and 77 by CsA plus androgen patients (1/48 vs 0/77, P =0.384). Both the total hematologic response and the better hematological response rates at 3-month (70.8% vs 45.5%, P =0.006 and 27.1% vs 10.4%, P =0.015, respectively) and 6-month (75.0% vs 55.8%, P =0.031 and 41.7% vs 22.1% P =0.020, respectively) after treatment were much higher in the standard IST group than that in CsA plus androgen group. The median time to transfusion independent of 36.5 (0-149) days in the standard IST group was significantly shorter than 98 (14-180) days in CsA plus androgen group ( P <0.001). Survival was comparable between the two groups (97.9% vs 100.0%, P =0.227). It was superior (71.2% vs 59.5%) but not significantly ( P =0.227) in event-free survival in standard IST group. Conclusions: CsA plus androgen was inferior to the standard IST of ATG/ALG and CsA regimen in treating TD-NSAA in terms of the hematologic response and the quality of response, despite of comparable short-term survival.

Objective: To evaluate the efficacy and safety of intensive immunosupressive therapy (IST) with antithymocyte/antilymphocyte globulin plus cyclosporine A in the treatment of older patients (≥60 years) with severe aplastic anemia (SAA)., Methods: The hematologic response and safety of sixteen older SAA patients treated with IST regimen in our hospital were retrospectively analyzed , and the factors affecting response were also explored., Results: A total of 16 older SAA patients were involved, the median age was 63.5 (60-79) years. Among them, 7 were VSAA and 9 were SAA; 9 patients received Rabbit anti- human thymocyte globulin (rATG), and 7 patients porcine anti- human lymphocyte globulin (pALG). Two patients died within 3 months after IST; at the 6 months after IST, 9 patients achieved hematology response and 5 patients had no response; overall response rate was 56.3%. Two (22%) of the 9 patients treated with rATG achieved hematology response; However, all 7 patients (100.0%) treated with pALG achieved hematology response. rATG/pALG associated adverse reactions were mild and easily managed., Conclusion: The older patients with SAA could still benefit from IST consisting of standard dose rATG/pALG with CsA, and the patients with VSAA had worse prognosis, pALG was inferior to rATG as a first treatment for SAA.

Objective: To analyze the clinical characteristics and to evaluate immunosuppressive therapy (IST) response and survival in hepatitis-associated aplastic anemia (HAAA)., Methods: We retrospectively analyzed clinical characteristics, IST response, long-term survival and clonal evolution in 41 HAAA patients, and compared those with age and bone marrow failure matched idiopathic aplastic anemia (IAA) patients., Results: The prevalence of HAAA among cases of SAA was 4.34% (41/944). The proportion of VSAA in HAAA cases was significantly higher than IAA (65.9% vs 39.4%, P=0.001). There was no significant difference in the prevalence of hemorrhage and infections between HAAA and IAA patients, but the duration of infection persistence in HAAA group was much longer than IAA group [21 (4-100) d vs 13 (3-139) d, P=0.048]. The absolute counts of CD3(+) T-cell, CD3(+)CD4(+)T-cell, CD3(+)CD8(+)T-cell and ratio of CD4(+) T-cell/CD8(+) T-cell in HAAA were significant lower than that in IAA patients. However, the percentage of CD3(+)CD8(+)T-cell in HAAA was significant higher than that in IAA (P <0.05). The total response in HAAA and IAA patients treated with IST were 34.1% vs 34.1% (P=1.000), 56.1% vs 53.7% (P=0.787), and 73.2% vs 68.3% (P=0.558) at 3, 6, 12 months after IST, respectively. There were no significant difference in 5-year overall survival and event-free survival between HAAA and IAA patients (90% vs 87.1%, P=0.700; 71.9% vs 62.4%, P=0.450)., Conclusion: HAAA was a rare distinct variant of aplastic anemia with more severe bone marrow failure and more severe imbalance of the T cell immune system than IAA. Treatment outcomes were comparable in patients with HAAA and IAA.

Objective: To compare the short-term therapeutic effect of different regimens combining recombinant human thrombopoietin (rhTPO) with immunosuppressive therapy (IST) applied in severe aplastic anemia (SAA)., Methods: The clinical data of newly diagnosed adult SAA patients treated with first-line IST, including 18 patients with rhTPO daily and 43 patients with rhTPO every other day, was analyzed retrospectively., Results: There was no significant difference between the basic clinical characteristics of the patients classified in different groups. The therapeutic effect was assessed 3 months and 6 months after IST. The statistical data revealed that the overall responses (OR) were not significantly different in daily group and every other day group (3 months: 50.0% vs 51.2%, P=0.934; 6 months: 77.8% vs 69.8%, P=0.525), while the good hematological response (CR+GPR) in SAA treated with rhTPO daily was significantly higher than that of patients treated with rhTPO every other day at 3 month after IST (38.9% vs 9.3%,P=0.011). RBC transfusion independence were not significantly different between the two groups after 4 weeks as well as 8 weeks treatment(4 weeks: 22.2% vs 18.6%,P=0.736; 8 weeks: 55.6% vs 46.5%,P=0.519), while platelet transfusion independence in rhTPO daily treated group was significantly higher than that in every other day group (88.9% vs 48.8%,P=0.003). In addition, there were no more adverse events observed in rhTPO daily group., Conclusions: It's more effective to promote hematopoietic recovery and reduce platelet transfusion dependence when rhTPO was daily used other than used every other day.

Objective: To explore more effective regimen for reducing early mortality of severe aplastic anemia (SAA) and improving therapeutic effectiveness., Methods: Antilymphocyte globulin/antithymocyte globulin (ALG/ATG) and cyclosporine A (CsA) (sequential intensified immunosuppressive therapy, SIIST), with or without hematopoietic growth factors (HGFs) were administered to 73 SAA patients in a prospective randomized clinical trial to test the effectiveness of the addition of HGFs for the patients., Results: The response rate of SIIST with HGFs group was significantly higher than that of SIIST alone group (89.2% vs 63.9%), with lower rates of early infection (24.3% vs 55.3%) and mortality (4.0% vs 16.7%), shorter duration of cytopenia and blood transfusion dependence and faster recovery of bone marrow hematopoiesis. The addition of HGFs to SIIST was tolerated well in all patients. There was no difference in the treatment outcome of the two groups with GM-CSF plus Epo or G-CSF plus Epo., Conclusion: The use of HGFs in combination with SIIST could reduce early infection and mortality rates and, therefore, improve the response rates in SAA patients.