scholarly journals Activity of eltrombopag in severe aplastic anemia

2018 ◽  
Vol 2 (21) ◽  
pp. 3054-3062 ◽  
Author(s):  
Phillip Scheinberg
Keyword(s):  
Aplastic Anemia ◽  
Single Agent ◽  
Complete Response ◽  
Severe Aplastic Anemia ◽  
Transfusion Independence ◽  
Thrombopoietin Receptor ◽  
Cd34 Cells ◽  
Insufficient Response ◽  
Marrow Cellularity

Abstract Since the approval of horse antithymocyte globulin (ATG) decades ago, there was a long hiatus in therapies with activity in severe aplastic anemia (SAA). This scenario changed in 2014 when eltrombopag, a thrombopoietin receptor agonist, was approved for SAA after an insufficient response to initial immunosuppressive therapy (IST). The basis for this approval was the observation of single-agent activity of eltrombopag in this patient population, where 40% to 50% recovered blood counts at times involving >1 lineage. The achievement of transfusion independence confirmed the clinical benefit of this approach. Increase in marrow cellularity and CD34+ cells suggested a recovery to a more functioning bone marrow. Further in its development, eltrombopag was associated with standard horse ATG plus cyclosporine in first line, producing increases in overall (at about 90%) and complete response rates (at about 40%) and leading to transfusion independence and excellent survival. Interestingly, best results were observed when all drugs were started simultaneously. The cumulative incidence of clonal cytogenetic abnormalities to date has compared favorably with the vast experience with IST alone in SAA. Longer follow-up will help in define these long-term risks. In this review, the development of eltrombopag in SAA will be discussed.

scholarly journals Activity of eltrombopag in severe aplastic anemia

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 450-456 ◽  
Author(s):  
Phillip Scheinberg
Keyword(s):  
Aplastic Anemia ◽  
Single Agent ◽  
Complete Response ◽  
Severe Aplastic Anemia ◽  
Transfusion Independence ◽  
Thrombopoietin Receptor ◽  
Cd34 Cells ◽  
Insufficient Response ◽  
Marrow Cellularity

AbstractSince the approval of horse antithymocyte globulin (ATG) decades ago, there was a long hiatus in therapies with activity in severe aplastic anemia (SAA). This scenario changed in 2014 when eltrombopag, a thrombopoietin receptor agonist, was approved for SAA after an insufficient response to initial immunosuppressive therapy (IST). The basis for this approval was the observation of single-agent activity of eltrombopag in this patient population, where 40% to 50% recovered blood counts at times involving >1 lineage. The achievement of transfusion independence confirmed the clinical benefit of this approach. Increase in marrow cellularity and CD34+ cells suggested a recovery to a more functioning bone marrow. Further in its development, eltrombopag was associated with standard horse ATG plus cyclosporine in first line, producing increases in overall (at about 90%) and complete response rates (at about 40%) and leading to transfusion independence and excellent survival. Interestingly, best results were observed when all drugs were started simultaneously. The cumulative incidence of clonal cytogenetic abnormalities to date has compared favorably with the vast experience with IST alone in SAA. Longer follow-up will help in define these long-term risks. In this review, the development of eltrombopag in SAA will be discussed.

High-Dose Cyclophosphamide in the Treatment of Children with Acquired Severe Aplastic Anemia Refractory to Conventional Immunosuppression.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3715-3715
Author(s):  
Jeffrey D. Hord ◽  
James A. Whitlock ◽  
Benjamin Carcamo ◽  
Ray C. Pais ◽  
Julie Blatt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Response Rate ◽  
Complete Response ◽  
Severe Aplastic Anemia ◽  
High Dose ◽  
Term Survival ◽  
Long Term Survival ◽  
Conventional Immunosuppression

Abstract Severe aplastic anemia (SAA), an illness characterized by the depletion of hematopoietic precursors within bone marrow leading to pancytopenia, has an overall mortality rate of >75% if left untreated. For children with human leukocyte antigen (HLA)-identical sibling donors, the treatment of choice for acquired SAA is allogeneic bone marrow transplant (BMT) with long-term survival of 70%–85%. For the 80% of children who lack suitable bone marrow donors, the standard treatment is immunosuppression with anti-thymocyte globulin (ATG), cyclosporine A (CSA), and often hematopoietic growth factors. Large series utilizing this immunosuppressive therapy have demonstrated a complete response rate of 60%–80%. When a patient does not have an HLA-identical sibling and fails to respond to conventional immunosuppression, options for further treatment are limited. One option is to pursue a matched unrelated donor (MUD) BMT, but matched donors are not available for all patients and long-term survival ranges between 20%– 60%. Treatment with high-dose cyclophosphamide is another option for refractory SAA patients that appears promising but has not been extensively studied in children. In 1999, a group of pediatric hematology centers joined together to study the use of high-dose cyclophosphamide for the treatment of children with acquired SAA not eligible for BMT and refractory to immunosuppression (Pediatric Aplastic Anemia Cooperative Trial #2). The goals of this study were to determine the response rate and toxicity associated with high-dose cyclophosphamide in children with refractory SAA. Between 10/1/99 and 6/3/02, 6 patients from 6 different centers were enrolled and received 4 days of intravenous cyclophosphamide (45 mg/kg/day), MESNA, and GM-CSF (250 mcg/m2/day SC) post-cyclophosphamide. The patient population consisted of 4 males and 2 females ranging in age from 2 to 18 years. The interval between diagnosis of SAA and cyclophosphamide treatment ranged from 8 to 88 months. All had failed to respond to earlier treatment with ATG and CSA. Twelve months following cyclophosphamide, there was 1 complete response (transfusion independent and normal blood counts), 1 partial response (transfusion independent but with moderate pancytopenia), 2 infectious deaths without recovery of blood counts, and 1 failure to respond. One patient was removed from the study before response could be assessed. High-dose cyclophosphamide in this population was associated with significant toxicity as 2 patients developed disseminated fungal infections within 30 days of starting therapy leading to death at day 18 in one. Another patient experienced grade 3 gingivitis/stomatitis lasting about 30 days. In summary, high-dose cyclophosphamide can lead to marrow recovery in some children with refractory SAA but is associated with the potential for life-threatening infectious complications, especially with fungus.

scholarly journals From chronic immune thrombocytopenia to severe aplastic anemia: recent insights into the evolution of eltrombopag

2017 ◽  
Vol 8 (5) ◽  
pp. 159-174 ◽  
Author(s):  
Harinder Gill ◽  
Raymond S. M. Wong ◽  
Yok-Lam Kwong
Keyword(s):  
Platelet Count ◽  
Aplastic Anemia ◽  
Immune Thrombocytopenia ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Pegylated Interferon ◽  
Severe Aplastic Anemia ◽  
Overall Response

Thrombopoietin (TPO) is the most potent cytokine stimulating thrombopoiesis. Therapy with exogenous TPO is limited by the formation of antibodies cross-reacting with endogenous TPO. Mimetics of TPO are compounds with no antigenic similarity to TPO. Eltrombopag is an orally-active nonpeptide small molecule that binds to the transmembrane portion of the TPO receptor MPL. Initial trials of eltrombopag have centered on immune thrombocytopenia (ITP), which is due to both increased destruction and decreased production of platelets. Eltrombopag at 25–75 mg/day has been shown to be highly effective in raising the platelet count in ITP with suboptimal response to immunosuppression and splenectomy. These successful results led to the exploration of eltrombopag in other thrombocytopenic disorders. In hepatitis C viral infection, eltrombopag raises the platelet count sufficiently enough to allow treatment with ribavirin and pegylated interferon. Because MPL is expressed on hematopoietic cells, eltrombopag use in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) might enhance leukemic proliferation. Clinical trials of eltrombopag in MDS and AML, however, have shown amelioration of thrombocytopenia without promoting disease progression. In severe aplastic anemia (SAA) not responding to immunosuppression with anti-thymocyte globulin (ATG) and cyclosporine, eltrombopag as a single agent at 150–300 mg/day results in an overall response rate of 40–70%. At high doses, adverse effects including pigmentation, gastrointestinal upset and hepatic derangement have become evident. Current studies have examined the first-line use of eltrombopag in combination with ATG in SAA. In a recent study, eltrombopag used at 150 mg/day with horse ATG resulted in an overall response rate of 90% in newly diagnosed SAA patients, with a complete response rate of about 50%. Clonal karyotypic aberrations are, however, found in 10–20% of SAA patients treated with eltrombopag. The safety and efficacy of eltrombopag in SAA require further evaluation, particularly when it is used with less intensive immunosuppression.

Trilineage Response in Severe Aplastic Anemia Following Long-Term Therapy with Recombinant Human Granulocyte Colony-Stimulating Factor

1993 ◽  
Vol 90 (3) ◽  
pp. 159-161 ◽  
Author(s):  
Eishi Ashihara ◽  
Chihiro Shimazaki ◽  
Toshiyuki Hirata ◽  
Katsunori Okawa ◽  
Naritoshi Oku ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Severe Aplastic Anemia ◽  
Term Therapy ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Long Term Therapy ◽  
Stimulating Factor

scholarly journals Nontransplant therapy for bone marrow failure

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Danielle M. Townsley ◽  
Thomas Winkler
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Single Agent ◽  
Telomere Attrition ◽  
Long Term Follow Up ◽  
Treatment Naïve

Abstract Nontransplant therapeutic options for acquired and constitutional aplastic anemia have significantly expanded during the last 5 years. In the future, transplant may be required less frequently. That trilineage hematologic responses could be achieved with the single agent eltrombopag in refractory aplastic anemia promotes new interest in growth factors after years of failed trials using other growth factor agents. Preliminary results adding eltrombopag to immunosuppressive therapy are promising, but long-term follow-up data evaluating clonal evolution rates are required before promoting its standard use in treatment-naive disease. Danazol, which is traditionally less preferred for treating cytopenias, is capable of preventing telomere attrition associated with hematologic responses in constitutional bone marrow failure resulting from telomere disease.

scholarly journals Recombinant Human Thrombopoietin Treatment Promotes Hematopoiesis Recovery in Patients with Severe Aplastic Anemia Receiving Immunosuppressive Therapy

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Huaquan Wang ◽  
Qi’e Dong ◽  
Rong Fu ◽  
Wen Qu ◽  
Erbao Ruan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Severe Aplastic Anemia ◽  
Red Blood Cell Transfusion ◽  
Overall Survival Rate ◽  
Normal Range ◽  
Hematologic Response ◽  
Transfusion Independence ◽  
Recombinant Human Thrombopoietin

Objective. To assess the effectiveness of recombinant human thrombopoietin (rhTPO) in severe aplastic anemia (SAA) patients receiving immunosuppressive therapy (IST).Methods. Eighty-eight SAA patients receiving IST from January 2007 to December 2012 were included in this retrospective analysis. Of these, 40 subjects received rhTPO treatment (15000 U, subcutaneously, three times a week). rhTPO treatment was discontinued when the platelet count returned to normal range. Hematologic response, bone marrow megakaryocyte recovery, and time to transfusion independence were compared.Results. Hematologic response was achieved in 42.5%, 62.5%, and 67.5% of patients receiving rhTPO and 22.9%, 41.6%, and 47.9% of patients not receiving rhTPO at 3, 6, and 9 months after treatment, respectively (P= 0.0665,P= 0.0579, andP= 0.0847, resp.). Subjects receiving rhTPO presented an elevated number of megakaryocytes at 3, 6, and 9 months when compared with those without treatment (P= 0.025,P= 0.021, andP= 0.011, resp.). The time to platelet and red blood cell transfusion independence was shorter in patients who received rhTPO than in those without rhTPO treatment. Overall survival rate presented no differences between the two groups.Conclusion. rhTPO could improve hematologic response and promote bone marrow recovery in SAA patients receiving IST.

scholarly journals Severe aplastic anemia: allogeneic bone marrow transplantation as first-line treatment

2018 ◽  
Vol 2 (15) ◽  
pp. 2020-2028 ◽  
Author(s):  
George E. Georges ◽  
Kris Doney ◽  
Rainer Storb
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Marrow Transplantation ◽  
Severe Aplastic Anemia ◽  
Unrelated Donor ◽  
Line Treatment ◽  
First Line ◽  
Matched Unrelated Donor ◽  
First Line Treatment

Abstract Treatment of severe aplastic anemia has improved significantly over the past 4 decades. This review will summarize the key areas of progress in the use of allogeneic hematopoietic cell transplantation and nontransplant immunosuppressive therapy (IST) for the treatment of aplastic anemia and then summarize the recommendations for first-line treatment. Based on recent data, we argue that guidelines for the initial treatment of patients with newly diagnosed severe aplastic anemia require revision. At the time of diagnosis, before beginning treatment, HLA typing should be done to identify a marrow donor among family members or in the unrelated donor registries, and a marrow transplant should be considered first-line therapy. The priority order of donor source for bone marrow transplantation is: (1) HLA-identical sibling, (2) HLA-matched unrelated donor, and (3) HLA-haploidentical donor if an HLA-matched unrelated donor is not rapidly available. Each of these donor marrow sources may be preferable to nontransplant IST. We make this recommendation because of the long-term persistent risk for disease relapse and secondary myelodysplastic syndrome or acute myeloid leukemia with the use of nontransplant IST for patients with aplastic anemia. In contrast, marrow transplantation is associated with high cure rates of aplastic anemia and a relatively low risk for graft-versus-host disease, with many patients now living for decades without the risk for disease recurrence or the development of clonal disorders. Implementation of this first-line treatment strategy will provide patients with severe aplastic anemia the best chance of long-term disease-free survival.

A Restrictive Platelet Transfusion Policy Allowing Long-Term Support of Outpatients With Severe Aplastic Anemia

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 3124-3126 ◽  
Author(s):  
Markus Sagmeister ◽  
Lic Oec ◽  
Jürg Gmür
Keyword(s):  
Aplastic Anemia ◽  
Platelet Transfusion ◽  
Severe Aplastic Anemia ◽  
Bleeding Complications ◽  
Outpatient Basis ◽  
Platelet Counts ◽  
The Mean ◽  
Restrictive Policy ◽  
Platelet Transfusions

Abstract The threshold for prophylactic platelet transfusions in patients with hypoplastic thrombopenia generally recommended in the standard literature is 20,000 platelets/μL. A more restrictive transfusion policy may be indicated in patients with chronic severe aplastic anemia (SAA) in need of long-term platelet support. We evaluated the feasibility and safety of a policy with low thresholds for prophylactic transfusions (≤5,000 platelets/μL in stable patients; 6,000 to 10,000 platelets/μL in cases with fever and/or hemorrhagic signs) combined with progressive lengthening of transfusion intervals (up to at least 7 days irrespective of the interim course of platelet counts). The study was based on a retrospective analysis of a total of 18,706 patient days with platelet counts ≤10,000/μL in patients with chronic SAA treated (for more than 3 months) on an outpatient basis. Altogether, 1,135 platelet transfusions were given, 88% at counts ≤10,000/μL and 57% at counts ≤5,000/μL. The mean transfusion interval was 10 days. During the period of observation, three major nonlethal bleeding complications occurred, which could be well controlled. We conclude that the restrictive policy with low transfusion thresholds and prolonged transfusion intervals proved feasible and safe in chronic SAA patients.

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