scholarly journals Allo-HSCT compared with immunosuppressive therapy for acquired aplastic anemia: Is superiority a one-sided understanding?

2020 ◽  
Author(s):  
Yangmin Zhu ◽  
Qingyan Gao ◽  
Jing Hu ◽  
Dongrui Guan ◽  
Xu Liu ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Comprehensive Evaluation ◽  
Clonal Evolution ◽  
Meta Analysis ◽  
First Line ◽  
Hematopoietic Stem ◽  
First Line Therapy ◽  
Risk Of Disease

Abstract Acquired aplastic anemia (AA) is a rare hematologic disease characterized by a profound pancytopenia and hypocellular bone marrow. To comprehensively compare the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with immunosuppressive therapy (IST) as a front-line treatment for patients with AA. We searched the Medline, Embase, and Cochrane Registry of Controlled Trials databases from January 2000 to March 2019. Studies comparing allo-HSCT with IST as a first-line therapy for patients with AA were included. Fifteen studies including a total of 5336 patients were included in the meta-analysis. The pooled hazard ratio (HR) for overall survival (OS) was 0.4 (95% CI 0.074–0.733, P = 0.016, I2 = 58.8%) and the pooled HR for failure-free survival (FFS) was 1.962 (95% CI 1.43–2.493, P = 0.000, I2 = 0%). The pooled relative risk (RR) for overall response rate (ORR) was 1.691 (95% CI 1.433–1.996, P = 0.000, I2 = 11.6%). Although survival was significantly longer among AA patients undergoing first-line allo-HSCT compared to those undergoing first-line IST, the selection of initial treatment for patients with newly diagnosed AA still requires comprehensive evaluation of donor availability, patient age, expected quality of life, risk of disease relapse or clonal evolution after IST, and potential use of adjunctive eltrombopag.

scholarly journals Allo-HSCT compared with immunosuppressive therapy for acquired aplastic anemia: Is superiority a one-sided understanding?

2020 ◽  
Author(s):  
Yangmin Zhu ◽  
Qingyan Gao ◽  
Jing Hu ◽  
Dongrui Guan ◽  
Xu Liu ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Comprehensive Evaluation ◽  
Clonal Evolution ◽  
Meta Analysis ◽  
First Line ◽  
Hematopoietic Stem ◽  
First Line Therapy ◽  
Risk Of Disease

Abstract Acquired aplastic anemia (AA) is a rare hematologic disease characterized by a profound pancytopenia and hypocellular bone marrow. To comprehensively compare the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with immunosuppressive therapy (IST) as a front-line treatment for patients with AA. We searched the Medline, Embase, and Cochrane Registry of Controlled Trials databases from January 2000 to March 2019. Studies comparing allo-HSCT with IST as a first-line therapy for patients with AA were included. Fifteen studies including a total of 5336 patients were included in the meta-analysis. The pooled hazard ratio (HR) for overall survival (OS) was 0.4 (95% CI 0.074–0.733, P = 0.016, I2 = 58.8%) and the pooled HR for failure-free survival (FFS) was 1.962 (95% CI 1.43–2.493, P = 0.000, I2 = 0%). The pooled relative risk (RR) for overall response rate (ORR) was 1.691 (95% CI 1.433–1.996, P = 0.000, I2 = 11.6%). Although survival was significantly longer among AA patients undergoing first-line allo-HSCT compared to those undergoing first-line IST, the selection of initial treatment for patients with newly diagnosed AA still requires comprehensive evaluation of donor availability, patient age, expected quality of life, risk of disease relapse or clonal evolution after IST, and potential use of adjunctive eltrombopag.

scholarly journals Allo-HSCT compared with immunosuppressive therapy for acquired aplastic anemia: Is superiority a one-sided understanding?

2020 ◽  
Author(s):  
Yangmin Zhu ◽  
Qingyan Gao ◽  
Jing Hu ◽  
Dongrui Guan ◽  
Xu Liu ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Comprehensive Evaluation ◽  
Clonal Evolution ◽  
Meta Analysis ◽  
First Line ◽  
Hematopoietic Stem ◽  
First Line Therapy ◽  
Risk Of Disease

Abstract Acquired aplastic anemia (AA) is a rare hematologic disease characterized by a profound pancytopenia and hypocellular bone marrow. To comprehensively compare the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with immunosuppressive therapy (IST) as a front-line treatment for patients with AA. We searched the Medline, Embase, and Cochrane Registry of Controlled Trials databases from January 2000 to March 2019. Studies comparing allo-HSCT with IST as a first-line therapy for patients with AA were included. Fifteen studies including a total of 5336 patients were included in the meta-analysis. The pooled hazard ratio (HR) for overall survival (OS) was 0.4 (95% CI 0.074–0.733, P = 0.016, I2 = 58.8%) and the pooled HR for failure-free survival (FFS) was 1.962 (95% CI 1.43–2.493, P = 0.000, I2 = 0%). The pooled relative risk (RR) for overall response rate (ORR) was 1.691 (95% CI 1.433–1.996, P = 0.000, I2 = 11.6%). Although survival was significantly longer among AA patients undergoing first-line allo-HSCT compared to those undergoing first-line IST, the selection of initial treatment for patients with newly diagnosed AA still requires comprehensive evaluation of donor availability, patient age, expected quality of life, risk of disease relapse or clonal evolution after IST, and potential use of adjunctive eltrombopag.

scholarly journals Allo-HSCT compared with immunosuppressive therapy for acquired aplastic anemia: Is superiority a one-sided understanding?

2019 ◽  
Author(s):  
Yangmin Zhu ◽  
Qingyan Gao ◽  
Jing Hu ◽  
Dongrui Guan ◽  
Xu Liu ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Comprehensive Evaluation ◽  
Clonal Evolution ◽  
Meta Analysis ◽  
Treatment Strategies ◽  
Line Treatment ◽  
Front Line ◽  
First Line ◽  
Hematopoietic Stem

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and immunosuppressive therapy (IST) are two major competing treatment strategies for acquired aplastic anemia (AA). Whether allo-HSCT is superior to IST as a front-line treatment for patients with AA has been a subject of debate. To comprehensively compare the efficacy and safety of allo-HSCT with IST as a front-line treatment for patients with AA. Methods: We searched the Medline, Embase, and Cochrane Registry of Controlled Trials databases from January 2000 to March 2019. Studies comparing allo-HSCT with IST as a first-line therapy for patients with AA were included. Results: Fifteen studies including a total of 5336 patients were included in the meta-analysis. The pooled hazard ratio (HR) for overall survival (OS) was 0.4 (95% CI 0.074–0.733, P = 0.016, I2 = 58.8%) and the pooled HR for failure-free survival (FFS) was 1.962 (95% CI 1.43–2.493, P = 0.000, I2 = 0%). The pooled relative risk (RR) for overall response rate (ORR) was 1.691 (95% CI 1.433–1.996, P = 0.000, I2 = 11.6%). Conclusion: Although survival was significantly longer among AA patients undergoing first-line allo-HSCT compared to those undergoing first-line IST, the selection of initial treatment for patients with newly diagnosed AA still requires comprehensive evaluation of donor availability, patient age, expected quality of life, risk of disease relapse or clonal evolution after IST, and potential use of adjunctive eltrombopag.

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 ◽  
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.

Alemtuzumab (Campath) Monotherapy for Severe Aplastic Anemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1167-1167 ◽  
Author(s):  
Phillip Scheinberg ◽  
Colin O Wu ◽  
Priscila Scheinberg ◽  
Olga Nunez ◽  
Elaine M Sloand ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Sample Size ◽  
Immunosuppressive Therapy ◽  
Primary Endpoint ◽  
Response Rate ◽  
Severe Aplastic Anemia ◽  
First Line ◽  
Hematologic Response ◽  
First Line Therapy ◽  
Line Therapy

Abstract Abstract 1167 Immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine (CsA) results in hematologic responses in 60–70% of severe aplastic anemia (SAA) patients and long-term survival among responders >80% (Young, Calado et al. 2006). With standard horse ATG (h-ATG) + CsA, success is limited because 1/3 of patients are unresponsive; 1/3 of responders relapse after achieving hematologic recovery; and clonal evolution to myelodysplasia occurs in 10–15% of cases. Retreatment success with rabbit ATG (r-ATG) in refractory patients has varied widely, from 30->70% (DiBona, Coser et al. 1999; Scheinberg, Nunez et al. 2006); for relapse, response to retreatment has been more consistent, at 50–60% (Schrezenmeier, Marin et al. 1993; Tichelli, Passweg et al. 1998; Scheinberg, Nunez et al. 2006). We hypothesized that the humanized anti-CD52 monoclonal antibody alemtuzumab (Campath) might be active in SAA due to its lymphocytotoxic properties and reported activity in various immune cytopenias (Willis, Marsh et al. 2001). At the Clinical Center of the National Institutes of Health, we tested alemtuzumab monotherapy in several research protocols for marrow failure. For refractory SAA, we conducted a prospective randomized study (starting in 2003) comparing r-ATG/CsA vs. alemtuzumab in patients unresponsive to initial h-ATG/CsA (www.clinicaltrials.govNCT00065260). Sample size was based on the primary endpoint, hematologic response at 6 months, through testing the proportions with 5% significance level and 80% power. A difference in response rate of 30% was hypothesized between these two regimens. Rabbit-ATG was administered at 3.5 mg/kg/day for 5 days with CsA to a trough of 200 – 400 ng/ml for 6 months, and alemtuzumab at 10 mg/d for 10 days, without CsA. In a recent interim analysis (25 patients in each arm), the response rate for each regimen was identical at 36% (95% CI, 15%-56%; p=1.00). The 1000-day survival was 86% (95% CI, 63%-95%) in the alemtuzumab arm and 65% (95% CI, 39%-82%) in the r-ATG arm (log-rank, p=0.25). Both regimens were well tolerated with no significant difference in serious adverse events between the two groups. Subclinical EBV and CMV reactivations commonly occurred after immunosuppressive therapy as described previously (Scheinberg, Fischer et al. 2007). Specific prophylactic or pre-emptive antiviral therapies were not instituted in any case. Based on this initial experience, we conducted a single arm open label trial investigating alemtuzumab in relapsed SAA (www.clinicaltrials.govNCT00195624). Sample size was calculated using a Two-Stage Minimax Design, based on the hypothesis that response to alemtuzumab would be >50%. After accruing 23 patients (first stage), hematologic response at 6 months (primary endpoint) was observed in 13 (56%; 95% CI, 37%-77%) and the study will proceed to the second stage. Based on the encouraging results in refractory and relapsed SAA, alemtuzumab was investigated in treatment-naïve patients in a study that randomized (1:1:1) among h-ATG/CsA, r-ATG/CsA, and alemtuzumab (www.clinicaltrials.govNCT00260689). After 16 patients were randomized to alemtuzumab, this arm of the study was discontinued at the recommendation of the DSMB as response was observed in only three patients and there were three early deaths. Alemtuzumab was also investigated in other settings in the context of these clinical trials. Of 13 patients unresponsive to r-ATG/CsA given as first line therapy, only one patient responded to rescue with alemtuzumab; and of 11 patients who were unresponsive to both h-ATG/CsA and r-ATG/CsA, response to alemtuzumab was observed in two (both responders had shown small but incremental improvement with each prior ATG course). Our results show that: 1) alemtuzumab is an active agent in SAA patients with relapsed or refractory SAA; 2) either r-ATG or alemtuzumab can rescue about 30% of patients unresponsive to initial h-ATG + CsA; 3) the response rate of alemtuzumab in relapsed SAA is comparable to the reported response rate of 50%-60% in this setting; 4) the salvage rate with alemtuzumab in those unresponsive to initial r-ATG/CsA appear low; and 6) alemtuzumab cannot be recommended as first line therapy of SAA outside of a clinical research protocol. Disclosures: Off Label Use: Alemtuzumab in severe aplastic anemia.

scholarly journals The Changing Landscape of Treatment in Pediatric Aplastic Anemia; A Single Institution's Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5082-5082 ◽  
Author(s):  
Georgia Avgerinou ◽  
Katerina Katsibardi ◽  
Maria Filippidou ◽  
Natalia Tourkantoni ◽  
Eleni Atmatzidou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cord Blood ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Immunosuppressive Treatment ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy

Abstract Introduction: Aplastic anemia (AA) is a rare syndrome of bone marrow failure characterized by peripheral blood pancytopenia and marrow aplasia. We report the clinical course and therapeutic approach of children with AA, who were treated in our Department within the last 4 years. Methods: Fifteen children (9 males/ 6 females) of mean age 7.64 years (range: 2 to 15 years) were diagnosed in our unit with AA since 2012. Diagnosis was established by bone marrow aspirate and biopsy and a normal bone marrow karyotype. Evaluation for underlying bone marrow failure syndromes, including Fanconi anemia, Shwachman-Diamond syndrome and paroxysmal nocturnal hemoglobinuria was performed in all cases. Results: Four children were identified with Fanconi anemia, both by cytogenetic and molecular analysis. Eleven children were diagnosed with acquired aplastic anemia (AAA); one probably after treatment with NSAIDs, one patient presented after influenza virus infection, while two patients presented also with transaminasemia of unknown etiology. First line therapy was hematopoietic stem-cell transplantation (HSCT), should an appropriate graft be available. In this respect, three patients (N: 3/4 ) with Fanconi anemia and one patient (N:1/11) with AAA were transplanted from a fully-matched sibling donor. One patient with AAA received autologous cord blood. The remaining ten patients (N: 10/15) received standard immunosuppressive therapy (antithymocyte globulin, cyclosporine-A and methylprednisolone). Eight of the 9 evaluable patients responded to therapy. Six of these patients also received treatment with eltrombopag, an oral thrombopoietin-receptor agonist, for at least six months. Eltrombopag was provided as off-label compassionate use and after having received approval from regulatory authorities. In these 6 patients, treatment with eltrombopag was well tolerated with no additive toxicity. Five patients showed progressive improvement of hematological values during the treatment with eltrombopag. Two patients with AAA, did not respond to immunosuppressive therapy, and subsequently underwent MUD-HSCT. One succumbed due to severe autoimmune hemolytic anemia, while the second has showed good engraftment, but with short post-BMT follow up time. Of note is, that one patient with Fanconi anemia showed full hematological recovery after immunosuppressive treatment. This patient, who was found to be homozygous for a FANC-E mutation, did not have any clinical stigmata. It is speculated that the unusual response to therapy may be due to its very mild clinical phenotype. Conclusions: Survival rates in severe AA have remarkably improved in the last decades due to allo-HSCT, immunosuppressive therapy and intense supportive care. This small series of children with AA underlines the option of new effective modalities. The use of autologous umbilical cord blood should be considered as an alternative first line therapy. Eltrombopag seems to improve platelet count and result in a tri-lineage response, in a manner similar to the one observed in adults with AA. Finally, the efficacy of immunosuppressive treatment in a patient with Fanconi anemia has not been previously described and warrants further evaluation. Disclosures Kattamis: Novartis: Honoraria, Research Funding; ApoPharma: Honoraria.

Hematopoietic Growth Factors In Aplastic Anemia Patients Treated with Immunosuppressive Therapy: Systematic Review and Meta-Analysis - 2010 Update.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1164-1164
Author(s):  
Ronit Gurion ◽  
Anat Gafter-Gvili ◽  
Liat Vidal ◽  
Mical Paul ◽  
Isaac Ben-Bassat ◽  
...  
Keyword(s):  
Systematic Review ◽  
Growth Factors ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Clonal Evolution ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Hematopoietic Growth Factors ◽  
Hematologic Response ◽  
All Cause Mortality

Abstract Abstract 1164 Background: Immunosuppressive therapy (IST) is the treatment for patients with severe aplastic anemia (SAA) not eligible for transplantation. It is controversial whether there is a role for hematopoietic growth factors (HGF) as an adjunct to IST in these patients. Objectives: A meta-analysis evaluating the role of HGF in this setting was published by our group in 2009. Since then, results of the largest conducted clinical trial by the Aplastic Anemia Working Party of the EBMT have been reported. We therefore updated our meta-analysis in order to evaluate if in 2010 there is still a role for the addition of HGF to IST in patients with SAA. Methods: Systematic review and meta-analysis of randomized controlled trials comparing treatment with IST and HGF to IST alone in patients with SAA. An updated search in The Cochrane Library, MEDLINE, conference proceedings and references was conducted in July 2010. Two reviewers independently assessed the quality of the trials and extracted data. Outcomes assessed were: all-cause mortality, overall hematologic response, infections and clonal evolution (transformation to myelodysplastic syndrome or acute leukemia). Relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. Results: Our search yielded 7 trials, randomizing 619 patients, including the 205 patients included in the EBMT trial recently published. Trials were conducted between the years 1991 and 2008. The IST regimen for most trials consisted of anti-thymocyte globulin, cyclosporine and steroids. The HGF in 6 trials was G-SCF and in 1 trial GM-CSF and erythropoietin. The addition of HGF to IST, compared with IST alone yielded no difference in all cause mortality at 100 days (RR 1.33, 95% CI 0.56–3.18) and at 5 years (RR 0.91, 95% CI 0.64–1.30, Fig.1). There was no difference in overall hematologic response at 12 months between the two arms (RR 1.16, 95% CI 0.91–1.47). There was no increase in the incidence of clonal evolution in the HGF arm compared to the control (RR 1.45, 95% CI 0.42–5.07). In addition there was no difference in the number of infections between both arms (RR 0.98, 95%CI 0.82–1.17). Conclusions: The addition of HGF to IST in SAA does not influence all-cause mortality, long term response, or the incidence of infections. The cumulative data in our updated meta-analysis is consistent with the results of our previous report. Therefore, HGFs should not be recommended routinely as an adjunct to IST for patients with SAA. Disclosures: Shpilberg: Roche: Consultancy, Honoraria.

scholarly journals Efficacy and Safety of Eltrombopag Combined with Cyclosporine As First-Line Therapy in Adults with Severe Acquired Aplastic Anemia: Results of the Interventional Phase 2 Single-Arm Soar Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2174-2174
Author(s):  
Carlos Vallejo ◽  
Jun Ho Jang ◽  
Carlo Finelli ◽  
Efreen Montaño Figueroa ◽  
Lalita Norasetthada ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Research Funding ◽  
Efficacy And Safety ◽  
First Line ◽  
Advisory Committees ◽  
Transfusion Independence ◽  
First Line Therapy ◽  
Insufficient Response ◽  
Grade 3

Abstract Background: Severe aplastic anemia (SAA) is a rare bone marrow failure disorder associated with significant morbidity and mortality. SAA is characterized by severe pancytopenia and a hypocellular (&lt;25%) bone marrow. The standard of care treatment is hemopoietic stem cell transplant or immunosuppressive therapy (IST) for patients (pts) who are ineligible for transplant. IST usually comprises an antithymocyte globulin (ATG) derived from horse or rabbit, and cyclosporine A (CsA). Although IST can be an effective treatment, individual intolerance, insufficient response, relapse, and clonal evolution remain significant limitations. The lack of global availability of the more effective horse ATG also leaves many pts with limited treatment options and poorer outcomes. In addition, pts with SAA often require transfusions which can be burdensome and negatively impact their quality of life. Eltrombopag (ETB) is indicated for use in pts with SAA who have had an insufficient response to IST (FDA PI, 2014) or are refractory to IST (EMA SmPC, 2015). More recently in the USA, ETB may also be used in combination with IST as first-line (1L) treatment (FDA PI, 2018). Aims: To assess the efficacy and safety of ETB + CsA (without ATG) as 1L therapy in adult pts with SAA. Methods: SOAR (NCT02998645) is a Phase 2, single-arm, multicenter, open-label study. Treatment-naive pts with SAA received ETB + CsA for 6 months; responders continued CsA therapy for an additional 24 months (later reduced to 18 months). The primary efficacy endpoint was overall response rate (ORR) by 6 months. ORR was defined as the proportion of pts with complete response ([CR] = absolute neutrophil count [ANC] ≥1000/μL AND platelet count ≥100,000/μL AND hemoglobin ≥10 g/dL) plus the proportion of pts with partial response ([PR] = any 2 of the following counts: ANC ≥500/μL; platelet count ≥20,000/μL; automated reticulocyte count ≥60,000/μL, but not sufficient for a CR). CR and PR were confirmed by 2 assessments ≥7 days apart; transfusion restrictions were also applied. For the primary endpoint to be considered 'clinically meaningful' at least 17/54 pts treated were required to have a response. Other endpoints included ORR by 3 months, ORR at 6 months (ie, confirmed response at the 6-month visit), and transfusion independence, which was defined as transfusion not being required in a period of ≥28 days for platelet transfusions and ≥56 days for red blood cell (RBC) transfusions. Results: Pts (N=54) had a median (interquartile range [IQR]) age of 55.0 (40.0-67.0) years and 63.0% were male. The majority of pts were White (40.7%) or Asian (40.7%). The median (IQR) duration of exposure to ETB and CsA was 5.7 (2.5-5.8) months and 5.7 (2.4-8.1) months, respectively, and the median (IQR) daily ETB dose was 150.0 (100.0-150.0) mg/day. In the full analysis set, the primary endpoint was met, with 25/54 pts having a CR or PR by 6 months (ORR 46.3%; 95% confidence interval [CI], 32.6-60.4%). Of the 25 responders, 2 (3.7%) achieved a CR by 6 months. ORR by 3 months was 40.7% (95% CI, 27.6-55.0%; n=22/54), and ORR at 6 months was 37.0% (95% CI, 24.3-51.3%; n=20/54). 70.4% of all pts qualified for ≥1 period of RBC and/or platelet transfusion independence by 6 months, including all 25 (100%) responders and 13/29 (44.8%) non-responders (Fig. 1). 40.7% of all pts (responders: 68.0%; non-responders: 17.2%) qualified for ≥1 period of RBC transfusion independence (corresponding percentages for platelet transfusion independence were the same as for the combined RBC and/or platelet endpoint). Adverse events (AEs) occurred in 52/54 (96.3%) pts; 45 (83.3%) pts experienced treatment-related AEs (TAEs), 23 (42.6%) of whom had a grade ≥3 TAE. The most common all-grade AEs were increased blood bilirubin (40.7%), nausea (29.6%), increased alanine aminotransferase (22.2%), and diarrhea (22.2%). Seven (13.0%) pts discontinued treatment due to grade ≥3 AEs. There were 8 on-treatment deaths (aplastic anemia [n=3]; COVID-19, hemorrhage, multi-organ dysfunction syndrome, pyrexia, and thrombosis [all n=1]); no deaths were considered treatment-related. Conclusion: Data from the SOAR study indicate that ETB + CsA may be beneficial for pts with SAA ineligible for transplant who cannot access or tolerate ATG. All responders and almost half of non-responders qualified for ≥1 period of transfusion independence by 6 months, suggestive of a decreased transfusion burden. No new safety signals were identified. Figure 1 Figure 1. Disclosures Vallejo: Novartis: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Finelli: Takeda: Consultancy; Celgene BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Calado: Agios: Membership on an entity's Board of Directors or advisory committees; AA&MDS International Foundation: Research Funding; Alexion Brasil: Consultancy; Instituto Butantan: Consultancy; Novartis Brasil: Honoraria; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees. Peffault De Latour: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals Inc: Consultancy, Honoraria; Swedish Orphan Biovitrum AB: Consultancy, Honoraria. Kriemler-Krahn: Novartis: Current Employment. Haenig: Novartis: Current Employment. Maier: Novartis: Current Employment. Scheinberg: Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BioCryst Pharmaceuticals: Consultancy; Roche: Consultancy; Abbvie: Consultancy. OffLabel Disclosure: In the United States, eltrombopag is a thrombopoietin receptor agonist indicated in combination with standard immunosuppressive therapy (ATG + CsA) for the first-line treatment of adult and pediatric patients aged 2 years and older with severe aplastic anemia (SAA). It is also indicated for the treatment of patients with SAA who have had an insufficient response to immunosuppressive therapy. The SOAR trial aims to assess the efficacy and safety of eltrombopag + CsA (without ATG) as first-line therapy in adult patients with SAA.

ДИАГНОСТИКА ХРОНИЧЕСКИХ ИНДУЦИРОВАННЫХ КРАПИВНИЦ

2019 ◽  
Author(s):  
E.Yu. Borzova
Keyword(s):  
Biological Therapy ◽  
Meta Analysis ◽  
Treatment Algorithm ◽  
The Novel ◽  
First Line ◽  
Systemic Reactions ◽  
Significant Impairment ◽  
Challenge Tests ◽  
First Line Treatment

Хронические индуцированные крапивницы имеют важное социально-экономическое значение вследствие риска развития системных реакций и значительного снижения качества жизни пациентов. Диагностика хронических индуцированных крапивниц основывается на анамнестических данных и проведении провокационных тестов. Современный протокол ведения больных хронической крапивницей включает применение неседативных антигистаминных препаратов. Международные согласительные документы по лечению крапивницы рекомендуют 4-кратное увеличение суточной дозы неседативных антигистаминных препаратов при их неэффективности в стандартных дозах. Данные мета-анализа указывают на эффективность омализумаба при хронических индуцированных крапивницах. В перспективе ожидается расширение арсенала генно-инженерной биологической терапии хронических индуцированных крапивниц.Chronic inducible urticarias are characterized by the risks of systemic reactions and a significant impairment of patients quality of life. The diagnosis of chronic inducible urticarias relies on the patients history and the challenge tests. A treatment algorithm for the management of chronic inducible urticarias includes nonsedating antihistamines as a first-line treatment. The international guidelines for the management of chronic inducible urticarias recommend updosing of nonsedating antihistamines up to four fold if standard doses are not effective. The meta-analysis suggests the efficacy of omalizumab in chronic inducible urticarias. In the prospect, the novel options of biological therapy for chronic inducible urticarias are expected.

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