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.

scholarly journals Unresponsive Severe Aplastic Anemia in a Young Patient: Case Report and Short Review of the Literature

2021 ◽  
Vol 6 (2) ◽  
pp. 116-119
Author(s):  
Oana Viola Bădulescu ◽  
Diana Popescu ◽  
Minerva Codruța Bădescu ◽  
Nicoleta Dima ◽  
Ana-Roxana Gănceanu-Rusu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Immunosuppressive Treatment ◽  
Family Doctor ◽  
Increase Response Rate ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Number Of Patients ◽  
Severe Pancytopenia

Abstract Aplastic anemia or medullary aplasia is a medical condition characterized by pancytopenia and is associated with a high prevalence of morbidity and mortality. In patients in whom bone marrow transplantation cannot be attempted, an immunosuppressive regimen is considered to be the first-line therapy. Also, the addition of eltrombopag from the first day of immunosuppressive treatment seems to significantly increase response rate. Unfortunately, there are a small number of patients who remain unresponsive to all these therapies. Here we present the case of a young woman who was referred by the family doctor complaining of marked physical asthenia, new onset dyspnea, and dizziness. Apart from a severe pancytopenia, no further changes have been brought to light by paraclinical investigations. After multiple secondary causes were excluded, the patient was diagnosed with idiopathic aplastic anemia. Even if bone marrow transplant was the first-line therapy in this case, because of the severe leukopenia, it was not possible to determine the HLA type. Therefore, the patient was prescribed immunosuppressive treatment. Despite the three drug-associated therapy (horse anti-thymocyte globulin, cyclosporin A, and eltrombopag), the response was unsatisfactory, with the persistence of severe pancytopenia.

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.

Marrow Failure

Hematology ◽  
2004 ◽  
Vol 2004 (1) ◽  
pp. 318-336 ◽  
Author(s):  
Grover C. Bagby ◽  
Jeffrey M. Lipton ◽  
Elaine M. Sloand ◽  
Charles A. Schiffer
Keyword(s):  
Bone Marrow ◽  
Immunosuppressive Therapy ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Dyskeratosis Congenita ◽  
Allogeneic Bone ◽  
Diagnosis And Management ◽  
Bone Marrow Failure Syndromes ◽  
Made In

Abstract New discoveries in cell biology, molecular biology and genetics have unveiled some of the pathophysiological mysteries of some of the bone marrow failure syndromes. Many of these discoveries have revealed why these syndromes show so much clinical overlap and some hold the potential for influencing the development of new therapies. In children and adults with pancytopenia and hypoplastic bone marrows proper differential diagnosis requires that some attention be directed toward defining molecular and cellular pathogenetic mechanisms because, once identified, some of these mechanisms will clearly suggest rational therapeutic approaches, treatment options that should be avoided, or both. In Section I, Drs. Jeffrey Lipton and Grover Bagby review the approach to diagnosis and management of patients with the inherited bone marrow failure syndromes, Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and the Shwachman-Diamond syndrome. Extraordinary progress has been made in identifying the genes bearing pathogenetically relevant mutations in these disorders, but slower progress has been made in defining the precise functions of the proteins these genes encode in normal cells, in part because it is increasingly obvious that the proteins are multifunctional. In practice, it is clear that in patients with dyskeratosis congenita and Fanconi anemia, the diagnosis must be considered not only in children but in adults as well. In Section II, Dr. Elaine Sloand outlines a very practical and evidence-based approach to diagnosis and management of acquired hypoplastic states emphasizing overlap between non-clonal and clonal hematopoiesis is such conditions. The pathogenesis of T lymphocyte–mediated marrow failure is presented as a clear-cut rationale for use of immunosuppressive therapy and stem cell transplantation. Practical management of patients with refractory disease with and without evidence of clonal evolution (either paroxysmal nocturnal hemoglobinuria [PNH] or myelodysplasia [MDS]) is presented. In Section III, the challenge of hypoplastic MDS is reviewed by Dr. Charles Schiffer. After reviewing the most up-to-date classification scheme, therapeutic options are reviewed, focusing largely on agents that have most recently shown some promising activity, including DNA demethylating agents, thalidomide and CC5013, arsenic trioxide, and immunosuppressive therapy. Here are also outlined the rationale and the indications for choosing allogeneic bone marrow transplantation, the only therapy with known curative potential.

Unexpected Fanconi Anemia Diagnosis in Patients with Bone Marrow Failure.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1056-1056
Author(s):  
Fernando O. Pinto ◽  
Thierry Leblanc ◽  
Gwenaelle Le Roux ◽  
Helene Dastot ◽  
Moema Santos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Clinical Features ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Somatic Mosaicism ◽  
Chromosome Breakage ◽  
Large Set ◽  
Chromosomal Breakage ◽  
Group A

Abstract Early diagnosis of Fanconi Anemia (FA) in patients with bone marrow failure is critical for optimal clinical management. However, the remarkably high clinical variability and the potential emergence of revertant hematopoietic cells (somatic mosaicism) can obscure and delay the diagnosis of FA. Here we addressed FA diagnosis in a prospective series of adult and pediatric patients who presented with bone marrow failure without clear overall clinical picture of FA. Sixty-six patients were classified into three groups: (1) bone marrow failure likely to be congenital, based on dysmorphic features or a family history [n=18], (2) aplastic anemia likely to be idiopathic [n=32], (3) patients with intermediate clinical features not classified into the former groups [n=16]. Of note, FA patients with typical clinical features were not included in the present study. FA diagnosis was evaluated using chromosome breakage test and FANCD2 immunoblot in PHA-stimulated-PBL. In addition, skin primary fibroblasts were analysed in order to overcome potential hematopoietic FA reversion. For that purpose, and considering that chromosome breakage tests are barely efficient in fibroblasts, we used FANCD2 immunoblot and also developped a new flow cytometry test based on MMC-sensitivity in fibroblasts (to detect downstream FA/BRCA groups). Using these approaches, we detected FA in 4 previously undiagnosed patients: a 35-years old patient from the congenital-like group; a 10-years old patient presenting as an idiopathic aplastic anemia without any FA signs; and two patients from the intermediate group: a 10-years old patient with an isolated thrombocytopenia, and a 50-years old patient presenting with pancytopenia/MDS and complete hematopoietic reversion. Importantly, FA diagnosis was definitely excluded in all other patients. In conclusion, we could identify a few unexpected FA cases in a series of patients with bone marrow failure. Therefore, the comprehensive use of a large set of tests is useful for accurate FA diagnosis. Classical chromosomal breakage tests in PBL appeared to be sufficient to exclude FA in idiopathic aplastic anemia, whereas fibroblast analysis can be necessary to definitely diagnose or exclude FA in other patients.

Efficacy of Cyclosporine Treatment in Patients with MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4608-4608
Author(s):  
Alina Kokhno ◽  
Elena Parovitchnikova ◽  
Elena Mikhailova ◽  
Yulia Olshanskaya ◽  
Irina Kaplanskaya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stable Disease ◽  
Response Rate ◽  
Bone Marrow Failure ◽  
Normal Karyotype ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Line Therapy

Abstract Myelodysplastic syndrome (MDS) represents a heterogenous group of myeloid neoplasms characterized by abnormal differentiation and maturation of myeloid cells, bone marrow failure and genetic instability. The recent clinical and laboratory investigations suggest that MDS is closely related to diseases in which the bone marrow failure is mediated at least in part by the immune system. The are few studies concerning the of efficacy of treatment of MDS pts with cyclosporine A (CSA) but they are limited to the group of pts with bone marrow hypoplasia. The aim of our study was to evaluate the efficacy of CSA treatment in MDS pts as first line or second line therapy. 48 pts with different forms of MDS were included in study. The group of first line CSA treatment included 30 pts, male-18/female-12, RA-3, RARS-1, RCMD-18, RAEB-7, RAEBt-1, 20-normal karyotype, 10-different abberations including: 5q−, 16q+, −7, 12q+, −Y, [11p+,7q−] and complex abb. Hypoplastic bone marrow was revealed in 15 pts, hyperplastic-8 pts, hypo/hyper-7 pts. Second line therapy group included 18 pts, male-9/female-9, RCMD-11, RARS-1, RAEB-5, RAEBt-1, normal karyotype-3, cytogenetic anomalies-13 (+8, 5q−,−7, +8 and complex abb.). Hypoplastic bone marrow was revealed in 12 pts, hyperplastic-4 pts, hypo/hyper-4 pts. The first line therapy consited of splenectomy in 8 pts, low doses of Ara-C-3, interferon-α-3, chemotherapy-2 and ATG-2 pts. CSA was applied at 5–10 mg/kg/day initially and then adjusted according to blood levels and toxicity. The maintenance dose was 1–3 mg/kg/day. Minimum time to response evaluation was one month. Complete response (CR) was defined as normal PB counts, BM aspirate; partial response-improvement of PB counts to 50% of normal and freedom from transfusions; stabilization-decrease of transfusion requirements and stabilization of PB counts for more then 1 month. Total response rate in first group was 60% (18 pts) with median follow up of 10 months (2–134). CR was estimated in 20% (6pts), median follow-up 72 months (44–134). 2 pts with CR are in clonal remission. 2 pts from response group developed acute leukemia (AL). 40% of pts showed no response.58% of pts without response developed RAEB or AL. 42% of pts were in stable disease and were treated with another modalities. The response rate in second group was 61% (11 pts) with median follow-up of 7 months (1–78). 22% (4 pts) achieved CR, median follow-up 60 months (43–78). 39% of pts showed no response. 71% from these pts (5) transformed to RAEB or AL. 2 pts remained in stable disease. In both groups response was registrated from 1 to 4 months from treatment initiation (median 3 months). CR was achieved in the majority of pts after 1 year of treatment. Response was achieved in 77% of pts with hypo/hyper and hypoplastic bone marrow and in 12% of pts with hyperplastic bone marrow. Overall survival was decreased in pts with more the 5% blasts in bone marrow (p=0,02 for 1st line group, p=0,075 for 2nd line group), and increased for pts with hypo and hypo/hyper bone marrow cellularity (p=0,002 for 1st line group). There was no impact of cytogenetics. We may conclude, that CSA demonstrates good efficacy in therapy of MDS pts, especially for pts with RA, RARS and RCMD with hypo and hypo/hypercellular bone marrow and reactive lymphoid nodules in bone marrow. It can be initiated as 1st or 2nd line therapy and should be continued at least for 3 months before evaluating of response.

Outcomes in Children with Severe Aplastic Anemia Receiving Bone Marrow Transplantation from an HLA-Matched Family Donor or Intensive Immunosuppressive Therapy As First-Line Treatment,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3421-3421 ◽  
Author(s):  
Nao Yoshida ◽  
Akira Kikuchi ◽  
Ryoji Kobayashi ◽  
Hiromasa Yabe ◽  
Yoshiyuki Kosaka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Cell Transplantation ◽  
Marrow Transplantation ◽  
Line Treatment ◽  
First Line ◽  
Family Donor ◽  
First Line Treatment

Abstract Abstract 3421 Bone marrow transplantation (BMT) from an HLA-matched family donor (MFD) is the treatment of choice for severe aplastic anemia (SAA) in children. For children without an MFD, immunosuppressive therapy (IST) with a combination of antithymocyte globulin and cyclosporine has been successful. However, this treatment approach is based on the results of comparative studies between these therapies conducted in the 1980s, and the outcomes of both BMT and IST have improved markedly over the past three decades. Therefore, updated evidence for treatment decisions in pediatric SAA is required. In the present study, we compared the outcomes of children with SAA who received IST (subjects enrolled in the prospective multicenter trials of IST conducted by the Japan Childhood Aplastic Anemia Study Group) or BMT from an MFD (subjects registered in the Transplant Registry Unified Management Program conducted by the Japan Society for Hematopoietic Cell Transplantation). The influence of potential risk factors on overall survival (OS) and failure-free survival (FFS) was assessed according to first-line treatment, time period of treatment (1992–1999 and 2000–2009), age and other variables related to each treatment. FFS was defined as survival with treatment response. Death, primary or secondary graft failure, relapse and secondary malignancy were considered treatment failures in patients who received BMT. Death, relapse, disease progression requiring stem cell transplantation from an alternative donor or 2nd IST, clonal evolution and evolution to paroxysmal nocturnal hemoglobinuria were considered treatment failures in patients who received IST. Between 1992 and 2009, 599 children with SAA younger than 17 years received BMT from an MFD (n=213) or IST (n=386) as first-line treatment. While the OS did not differ between patients receiving IST and BMT (88±2% vs. 90±2% at 15 years), FFS was significantly inferior in patients receiving IST as compared to those receiving BMT (54±3% vs. 84±3% at 15 years, P<0.0001). There was no significant improvement in outcomes over the two time periods; OS and FFS at 10 years in 1992–1999 vs. 2000–2009 were 87±2% vs. 93±2% and 66±3% vs. 67±3%, respectively. On multivariate analysis, age <10 years was identified as a favorable factor for OS (P=0.007) and choice of first-line IST was the only unfavorable factor for FFS (P<0.0001). These updated data support the current algorithm for treatment decisions, which recommends BMT when an MFD is available. Disclosures: No relevant conflicts of interest to declare.

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