scholarly journals Pediatric Patients with Severe Aplastic Anemia Treated with Combined Immunosuppressive Therapy, Eltrombopag and Eculizumab and Their Clinical Course to Stem Cell Transplant

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-13
Author(s):  
Kazuhiro Sabet ◽  
Arun Ranjan Panigrahi
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Pediatric Patients ◽  
The Other ◽  
Severe Aplastic Anemia ◽  
Clone Size ◽  
A Minor ◽  
Pnh Clone

Acquired aplastic anemia (AA) in children is a rare disorder characterized by pancytopenia and hypocellular bone marrow. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoetic stem cell (HCT) disorder characterized by complemented-mediated hemolysis, thrombosis and bone marrow failure secondary to deficiency of glycosylphosphatidylinositol-anchored proteins (GPI-AP) on hematopoetic stem cells. PNH and acquired AA are closely related; up to 50% of patients with AA have detectable PNH-clones at the time of diagnosis and small percentage of them can have clonal expansion throughout their disease course requiring close monitoring. Current standard therapy for severe aplastic anemia (SAA) patients without matched related donor (MRD) is immunosuppressive therapy (IST) regimen with anti-thymoglobulin (ATG), cyclosporine (CSA), and recent addition of eltrombopag. Eculizumab is a recombinant humanized monoclonal antibody that blocks complement protein C5 and prevents cell lysis. While it has been shown to be effective in children with PNH, concomitant treatment with IST for patients with SAA is unknown. To our knowledge, there has been no pediatric data on combined IST, eltrombopag and eculizumab treatment for children with AA with clinically significant PNH clones. Here we retrospectively reviewed three pediatric patients with SAA with PNH clones treated with IST, eltrombopag and eculizumab and their unique clinical courses. Two out of three patients had high PNH clone size and were started on eculizumab prior to IST with improvement in transfusion intervals. Of the two, one had decrease in PNH clone size after IST but the other patient's clone size continued to increase despite two courses of IST. Finally, the third patient had a minor PNH clone and was not started on eculizumab prior to IST. He remained asymptomatic for over a year until he developed symptomatic PNH with large clone size and aplastic bone marrow. His clone size continued to increase with no improvement in transfusion frequency despite being started on eculizumab. However, steroids were started based on anecdotal literature and his transfusion frequency decreased subsequently. All three patients are in the process of going through matched unrelated donor stem cell transplants. Several studies have reported the presence of a minor PNH clone at the time of AA diagnosis was associated a favorable response to IST. In this case series, the patient with the smallest PNH clone size at the time of diagnosis of SAA had the best response to IST compared to the other two patients who had larger PNH clone populations. These findings suggest that even though minor PNH population may lead to better response to IST compared to absence of the clone, the correlation between clone size and prognosis is unclear. Further study with larger sample size is needed to investigate this relationship. However, regardless of the population size, all three patients were able to prolong transfusion intervals using eculizumab without significant side effects. As the adoption of eltrombopag with standard IST is evolving with ongoing study, the efficacy of incorporating eculizumab to decrease transfusion frequency in patients with PNH-clone in addition to eltrombopag/IST regimen should be further investigated. Disclosures No relevant conflicts of interest to declare.

Pegfilgrastmin in Children with Severe Aplastic Anemia during Immunosuppressive Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3766-3766
Author(s):  
Katarzyna Pawelec ◽  
Michal J. Matysiak
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Partial Remission ◽  
Antithymocyte Globulin ◽  
Well Being ◽  
The Other ◽  
Severe Aplastic Anemia ◽  
Severe Neutropenia ◽  
Days Of Therapy

Abstract Severe neutropenia and infections connected with leukopenia are same of the main complications in immunosuppressive therapy (IST) of severe aplastic anemia (SAA). Granulocyte-colony-stimulating factors are currently given as supportive therapy in SAA protocol treatment beside antithymocyte globulin and cyclosporine A (CSA). We present four cases of girls aged 6–16 years with SAA without family bone marrow donors, who received pegfilgrastmin in IST. The protocol included: antithymocyte globulin (rabbit) 3.75mg/kg/bw iv for 5 days, CSA 5mg/kg/bw orally for 180 days and pegfilgrastmin (Neulasta-Amgen) 6mg in patients over 45kg and 100μg/kg in children less than 45 kg every 10 days sc until absolute neutrophil count (ANC)reached > 1.5x109/l. Blood was monitored every 7 days during therapy. Two patients received 4 doses of pegfilgrastmin. After this therapy the ANC level was normal without any decreases and we observed slow, gradual rise ANC in this girls In these patients there was a complete remission on day 180 of treatment and both are still in remission month 34. The other two patients received 6 doses of pegfilgrastmin. We observed fairly rapid rise and fall of leukocytes during the first 30 days of therapy. The ANC level became normal on day 70 of treatment. One of the patients is now in partial remission day 320. The other girl did not respond to the first course of IST and she received the second course of IST due to the lack of an unrelated bone marrow donor. Pegfilgrastmin was also administered during this therapy. After 3 doses of pegfilgrastmin leukocyte level rose to 5.3x109/l and ANC level to 2.3x109/l. At present the patient is in partial remission and is still receiving CSA day 210. Pegfilgrastimn administered every 10 days was well tolerated by all four patients and there were no adverse events. We observed that pegfilgrastmin was as effective as filgrastmin which was previously administered. No changes were noted during ANC recovery. However administration of pegfilgrastmin reduced the number of injections given and improved the patient’s well-being.

Paroxysmal Nocturnal Hemoglobinuria Clones in Children with Acquired Aplastic Anemia: A Multicentric Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1269-1269
Author(s):  
Fabio Stefano Timeus ◽  
Nicoletta Crescenzio ◽  
Alessandra Doria ◽  
Luiselda Foglia ◽  
Sara Pagliano ◽  
...  
Keyword(s):  
Stem Cell ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Clonal Expansion ◽  
Becton Dickinson ◽  
Clone Size ◽  
Favourable Response ◽  
Immune Mediated ◽  
Pnh Clone

Abstract Abstract 1269 Introduction. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic disorder characterized by the clonal expansion of a PIG-A mutated stem cell and consequent defective synthesis of glycosil phosphatidyl-inositol-anchored proteins, complement-mediated hemolysis, increased incidence of thrombosis, bone marrow failure. PNH and acquired aplastic anemia (AA) are closely related and a reciprocal progression is possible. A relative resistance of the PNH stem cell to the immune-mediated damage can explain the PNH clonal expansion in AA. High resolution flow cytometry analysis (FCA) has revealed a high incidence of minor PNH clones in adult AA patients at diagnosis, predictive for some Authors of a favourable response to the immunosuppressive therapy (IST) (Maciejevki et al, 2001; Ishiyama et al, 2003; Sugimori et al, 2006). “Pure” PNH is a very rare disease in children. Only a few studies have so far evaluated longitudinally PNH clones in pediatric AA patients. Materials and Methods. Ninety AA patients diagnosed in 8 AIEOP (Italian Association of Pediatric Hematology-Oncology) Centers (age at diagnosis 1–20 years, median =10.8, 51 severe AA, 30 very severe AA, 9 non severe AA) were studied: forty-one since diagnosis, 25 during IST, 20 off therapy and 4 selected cases after hematopoietic stem cell transplantation (HSCT). Among the patients followed since diagnosis, 8 received an HLA matched sibling donor HSCT as first line therapy, whereas the other 33 patients were treated with IST according to EBMT protocols (anti-lymphocyte globulin/anti-thymocyte, ciclosporin ± granulocyte colony stimulating factor). The study started in 1998. Peripheral blood PNH cells were detected by lack of CD59 expression on granulocytes by a two-color FCA for CD59 (clone p282-FITC Becton-Dickinson) and CD11b (clone D12-PE Becton-Dickinson); at least 105 cells were analyzed, for a total of 1104 tests. The presence of a population CD11b+/CD59- > 0.15% was defined as abnormal; the cut off value was established in 1998 by evaluating 87 normal controls (PNH clones: median = 0.001%, mean+2SD=0.10%). Since 2009 FCA results were confirmed by more sensitive techniques with three or six-color sequential gating analysis for CD45/33/66b or CD45/33/15/24/14/FLAER. Results. A PNH+ clone was observed in 15 patients (36.6%) at diagnosis (clone size 0.17–10.4%), in 10 patients (40%) during IST (clone size 0.16–12.6%) and in 8 patients (40%) off-therapy (clone size 0.16–4.0%). The presence of a PNH+ clone at diagnosis did not predict a favourable response to IST, both in ALG and ATG-treated patients. In 33 patients (16 at diagnosis, 9 in IST, 8 off therapy), the presence of the PNH clone was sporadic or intermittent, whereas in 13 patients (9 at diagnosis, 3 in IST, 1 off therapy) the clone persisted for more than 3 following controls (follow up 6–60 months). Among the 26 PNH- patients at diagnosis, in 10 a PNH clone (clone size 0.16–1.7%) appeared later during IST. Among the 25 patients studied during IST, in one patient PNH clone appearance was associated with the tapering of cyclosporine (figure 1), in two with the relapse when off therapy. In one out of 4 patients treated with HSCT, a PNH clone appeared at time of relapse and disappeared after starting IST with cyclosporine (figure 2). A mild hemolysis was observed in the only 2 patients with a major PNH clone (clone size 12.6 and 10.4% respectively). No thrombotic events were reported. Conclusions. We have observed a significant incidence of minor PNH clones in pediatric AA at diagnosis, as reported in adults. Whereas previous studies in adults correlated the presence of pre-treatment minor PNH clones with a favourable response to IST, we do not confirm those observations both in the present multi-centre as in our previous single-centre study (Timeus et al, 2010), in agreement with Yoshida et al (2008) and Scheinberg et al (2010). The appearance of a PNH clone in a PNH- patient at diagnosis is described as uncommon (Sugimori et al, 2009), however in our series this was observed in 38% of previously PNH- patients. In AA the presence of PNH clones seems related to complex interactions between stem cells, immune-mediated damage and immunosuppressive therapy. A periodic screening for PNH clones in patients with AA is recommended, permitting modulation in IST, early identification of major PNH clones and prompt diagnosis of a frank PNH. Disclosures: Timeus: Alexion Pharma Italy s.r.l.: Research Funding. Dufour:Pfizer: Consultancy.

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.

Erythrocytosis after Allogeneic Bone Marrow Transplantation in the Patients with Severe Aplastic Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5327-5327
Author(s):  
Soo-Jeong Park ◽  
Chi-Wha Han
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Severe Aplastic Anemia ◽  
Allogeneic Bone ◽  
Laboratory Findings ◽  
Normal Ranges ◽  
Serum Erythropoietin Level

Abstract Severe aplastic anemia (sAA) is a bone marrow failure disorder which is mostly a consequence of immunologically mediated stem cell destruction. Stem cell transplantation (SCT) from a histocompatible sibling is a treatment of choice for this disease but major obstacles in success of allogeneic SCT include graft-versus-host disease (GVHD), graft rejection and treatment related toxicities. We describe two cases of post-transplant erythrocytosis in severe aplastic anemia. About 5 years later, following HLA-matched sibling transplantation, the patients (45-year-old male and 43-year-old male) developed a sustained increase in hemoglobin (>17 g/dL) and hematocrit (> 50%), an increase in the frequency of headache, and new onset of dizziness and malaise. Laboratory findings demonstrated normal ranges of other blood components and serum erythropoietin level, and they did not have smoking or other drugs. Also, they did not have a hepatosplenomegaly or other organ diseases. We initiated a therapeutic phlebotomy program (400 ml q 2–4 weeks and then q 2–3 months for 5 years) in order to lower the hematocrit to available values (Hb < 14.5 g/dL), and to induce iron deficiency (Fig 1). Repeated phlebotomy resulted in a decrease in symptoms and a total volume of blood venesection is about 9,200 – 11,200 ml so far. Figure 1. Hemoglobin change after bone marrow transplantations. Figure 1. Hemoglobin change after bone marrow transplantations.

Bone Marrow Histology in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4215-4215
Author(s):  
Sandra van Bijnen ◽  
Konnie Hebeda ◽  
Petra Muus
Keyword(s):  
Bone Marrow ◽  
Mast Cells ◽  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Plasma Cells ◽  
Bone Marrow Failure ◽  
Clone Size ◽  
Immune Mediated ◽  
Lymphoid Nodules ◽  
Pnh Clone

Abstract Abstract 4215 Introduction Paroxysmal Nocturnal Hemoglobinuria (PNH) is a disease of the hematopoietic stem cell (HSC) resulting in a clone of hematopoietic cells deficient in glycosyl phosphatidyl inositol anchored proteins. The clinical spectrum of PNH is highly variable with classical hemolytic PNH at one end, and PNH in association with aplastic anemia (AA/PNH) or other bone marrow failure states at the other end. It is still largely unknown what is causing these highly variable clinical presentations. Immune-mediated marrow failure has been suggested to contribute to the development of a PNH clone by selective damage to normal HSC. However, in classic PNH patients with no or only mild cytopenias, a role for immune mediated marrow failure is less obvious. No series of trephine biopsies has been previously documented of patients with PNH and AA/PNH to investigate the similarities and differences in these patients. Methods We have reviewed a series of trephine biopsies of 41 PNH patients at the time the PNH clone was first detected. The histology was compared of 27 patients with aplastic anemia and a PNH clone was compared to that of 14 patients with classic PNH. Age related cellularity, the ratio between myeloid and erythroid cells (ME ratio), and the presence of inflammatory cells (mast cells, lymphoid nodules and plasma cells) were evaluated. The relation with clinical and other laboratory parameters of PNH was established. Results Classic PNH patients showed a normal or hypercellular marrow in 79% of patients, whereas all AA/PNH patients showed a hypocellular marrow. Interestingly, a decreased myelopoiesis was observed not only in AA/PNH patients but also in 93% of classic PNH patients, despite normal absolute neutrophil counts (ANC ≥ 1,5 × 109/l) in 79% of these patients. The number of megakaryocytes was decreased in 29% of classic PNH patients although thrombocytopenia (< 150 × 109/l) was only present in 14% of the patients. Median PNH granulocyte clone size was 70% (range 8-95%) in classic PNH patients, whereas in AA/PNH patients this was only 10% (range 0.5-90%). PNH clones below 5% were exclusively detected in the AA/PNH group. Clinical or laboratory evidence of hemolysis was present in all classical PNH patients and in 52% of AA/PNH patients and correlated with PNH granulocyte clone size. Bone marrow iron stores were decreased in 71% of classic PNH patients. In contrast, increased iron stores were present in 63% of AA/PNH patients, probably reflecting their transfusion history. AA/PNH patients showed increased plasma cells in 15% of patients and lymphoid nodules in 37%, versus 0% and 11% in classic PNH. Increased mast cells (>2/high power field) were three times more frequent in AA/PNH (67%) than in PNH (21%). Conclusion Classic PNH patients were characterized by a more cellular bone marrow, increased erythropoiesis, larger PNH clones and clinically by less pronounced or absent peripheral cytopenias and more overt hemolysis. Decreased myelopoiesis and/or megakaryopoiesis was observed in both AA/PNH and classic PNH patients, even in the presence of normal peripheral blood counts, suggesting a role for bone marrow failure in classic PNH as well. More prominent inflammatory infiltrates were observed in AA/PNH patients compared to classical PNH patients. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2437-2437
Author(s):  
Zonghong Shao ◽  
Qi'e Dong ◽  
Rong Fu
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Platelet Transfusion ◽  
Conflicts Of Interest ◽  
Severe Aplastic Anemia ◽  
Hematologic Response ◽  
Patient Will ◽  
Red Cell Transfusion ◽  
Recombinant Human Thrombopoietin

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

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