Recombinant humanized anti-IL-2 receptor antibody (daclizumab) produces responses in patients with moderate aplastic anemia

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3584-3586 ◽  
Author(s):  
Jaroslaw P. Maciejewski ◽  
Elaine M. Sloand ◽  
Olga Nunez ◽  
Carol Boss ◽  
Neal S. Young
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Aplastic Anemia ◽  
Neutrophil Count ◽  
Bone Marrow Failure ◽  
Interleukin 2 ◽  
Immunosuppressive Agent ◽  
Solid Organ ◽  
Bone Marrow Failure Syndrome ◽  
Humanized Monoclonal Antibody

AbstractIn contrast to severe aplastic anemia (sAA), the appropriate management of patients with moderate pancytopenia is unclear. In this study, we examined the efficacy of a humanized monoclonal antibody recognizing interleukin-2 receptor (daclizumab), which has proven to be a successful immunosuppressive agent in solid organ and bone marrow transplantation. We treated 17 patients with moderate aplastic anemia (mAA) with 1 mg/kg every 2 weeks for 3 months. mAA was defined as depression of 2 of the 3 blood counts: absolute neutrophil count 1200/mm3 or less, platelet count 70 000/mm3 or less, hemoglobin level 8.5 g/dL or lower, and absolute reticulocyte count 60 000/mm3 or less. The primary end point of our protocol was a hematologic response in at least one affected peripheral blood value. Daclizumab had little toxicity. Six of the 16 (38%) evaluable patients responded to treatment. Two patients with previously chronic disease showed complete return of normal counts, which were sustained for more than 2 years following treatment. Four patients had single-lineage responses. Two previously transfusion-dependent patients became transfusion independent; one patient with many neutropenia-related infections had a normal neutrophil count following treatment. Daclizumab appears safe; its efficacy in this pilot protocol suggests that expanded study of this monoclonal antibody in immune-mediated bone marrow failure syndrome is warranted. (Blood. 2003; 102:3584-3586)

Hepatitis-associated Aplastic Anemia Presenting as a Familial Bone Marrow Failure Syndrome

2009 ◽  
Vol 31 (11) ◽  
pp. 884-887 ◽  
Author(s):  
Vicky Rowena Breakey ◽  
Stephen Meyn ◽  
Vicky Ng ◽  
Christopher Allen ◽  
Inderjeet Dokal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Bone Marrow Failure Syndrome

scholarly journals Aplastic anemia: immunosuppressive therapy in 2010

2011 ◽  
Vol 3 (2s) ◽  
pp. 7 ◽  
Author(s):  
Antonio M. Risitano ◽  
Fabiana Perna
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
State Of The Art ◽  
Bone Marrow Failure ◽  
Standards Of Care ◽  
Bone Marrow Failure Syndrome ◽  
Clinical Observations ◽  
Immune Mediated ◽  
Experimental Works ◽  
Current Standards

Acquired aplastic anemia (AA) is the typical bone marrow failure syndrome characterized by an empty bone marrow; an immune-mediated pathophysiology has been demonstrated by experimental works as well as by clinical observations. Immunusuppressive therapy (IST) is a key treatment strategy for aplastic anemia; since 20 years the standard IST for AA patients has been anti-thymocyte globuline (ATG) plus cyclosporine A (CyA), which results in response rates ranging between 50% and 70%, and even higher overall survival. However, primary and secondary failures after IST remain frequent, and to date all attempts aiming to overcome this problem have been unfruitful. Here we review the state of the art of IST for AA in 2010, focusing on possible strategies to improve current treatments. We also discuss very recent data which question the equality of different ATG preparations, leading to a possible reconsideration of the current standards of care for AA patients.

scholarly journals Outcomes of Haploidentical Stem Cell Transplantation in Patients with Fanconi Anemia; A Systematic Review

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4308-4308
Author(s):  
Zunairah Shah ◽  
Israr Khan ◽  
Ali Shahbaz Baloch ◽  
Talha Awal ◽  
Sobia Aamir ◽  
...  
Keyword(s):  
Systematic Review ◽  
Bone Marrow ◽  
Fanconi Anemia ◽  
Research Funding ◽  
Bone Marrow Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Solid Organ ◽  
Bone Marrow Failure Syndrome ◽  
Post Transplant

Abstract Introduction Fanconi anemia (FA) is the most common inherited cause of bone marrow failure syndrome, with an incidence of approximately 1 out of 100,000 births per year and a prevalence of 1 in 360 000 live births. Clinical presentation is variable, ranging from classic Fanconi phenotype to absence of somatic abnormalities. Despite advances in understanding disease genetics and pathogenesis, hematopoietic stem cell transplant (HSCT) remains the only curative treatment option for FA patients. However, the future risk of solid organ malignancies persists post-transplant. Although outcomes of allogeneic HSCT for FA are improving steadily but remains suboptimal and often limited by donor availability- especially in countries lacking matched unrelated donor registry. For patients lacking a suitable donor, a trial of androgen is considered but is not curative, and around half of patients will not respond. Haploidentical HSCT has been successfully utilized in the management of acquired severe aplastic anemia and hematological malignancies but only limited published literature is available on its use in inherited bone marrow failure syndromes. We conducted this systematic review to explore survival outcomes of FA patients receiving haploidentical HSCT to assess feasibility of this treatment for patients lacking a matched donor. Methods We conducted a literature search on Pubmed, Cochrane, Google Scholar, open grey, and embase databases using the keywords; Haploidentical Transplant and Fanconi anemia. We screened 236 articles according to the Prisma diagram. After thoroughly reading the titles and abstracts, 13 articles were included for data extraction, and results were compiled. Results We analyzed thirteen studies with haploidentical transplant as a treatment for FA, 7 were retrospective, and 6 were prospective. Diagnosis of FA was established by chromosomal breakage analysis and genetic mutation testing. The preferred donor for a haploidentical transplant was a first-degree relative and mother/sibling in most cases. The total number of patients with FA and other disorder who received haploidentical transplants were n=340. The median age at HSCT was 6.7 (0.25-44) years. Two hundred six were male, and 134 were female. The most common conditioning regimen for FA patients was fludarabine, cyclophosphamide, and total body irradiation (TBI) followed by anti-thrombocyte globulin. Mehta. et al. evaluated haploidentical transplant without TBI in the conditioning regimen. The most common regimen to prevent graft versus host disease (GVHD) was cyclosporin and mycophenolate mofetil. Uppulur. R et al., Bonfim. C et al., Thakar. M.S et al. and Ayas, M et al. also used post-transplant cyclophosphamide for in vivo T cell depletion. Zubicaray. J et al and Strocchio. L et al. did not use any post-transplant therapy. Cumulative Overall survival reported was 79.1%. Cumulative acute GVHD was seen in 38.2%, while cumulative chronic GVHD was seen in 18.6% of patients. The most common adverse events were acute and chronic GVHD, Evans syndrome, steroid-induced osteoporosis, and diabetes. Respiratory syncytial virus, pneumonia, candida sepsis reactivation, hemorrhagic cystitis, and mucositis were the most common infections. Conclusion Fanconi anemia is an inherited bone marrow failure syndrome with somatic abnormalities and increased risk of hematological and solid organ malignancies. In FA, allogeneic hematopoietic cell transplantation (HCT) has been shown to restore normal hematopoiesis in patients with matched related donor HCT and has shown excellent long-term survival. Currently, limited data is available reporting outcomes of haploidentical HSCT for FA patients. More studies are required to establish safety and efficacy profiles. Figure 1 Figure 1. Disclosures Anwer: Allogene Therapeutics: Research Funding; GlaxoSmithKline: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; BMS / Celgene: Honoraria, Research Funding.

Mutations in the RNA Component of Telomerase, TERC, in Children with Aplastic Anemia and Myelodysplastic Syndrome: An NMDP Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3736-3736
Author(s):  
Joshua J. Field ◽  
Philip J. Mason ◽  
Yvonne J. Barnes ◽  
Allison A. King ◽  
Monica Bessler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Aplastic Anemia ◽  
Stem Cell Transplant ◽  
Bone Marrow Failure ◽  
Juvenile Myelomonocytic Leukemia ◽  
Cell Transplant ◽  
Bone Marrow Failure Syndrome ◽  
Base Pair Deletion

Abstract Mutations in TERC, the RNA component of telomerase, result in autosomal dominant dyskeratosis congenita (DC), a rare bone marrow failure syndrome. DC is clinically heterogeneous and TERC mutations have been detected in a subset of patients previously diagnosed with idiopathic aplastic anemia (AA) and myelodysplastic syndrome (MDS). Unrecognized TERC mutations are clinically relevant as patients with DC respond poorly to immunotherapy and have an increased risk of complications following conventional conditioning for stem cell transplant (SCT). We aimed to determine the frequency of TERC mutations in pediatric patients with AA and MDS who require a SCT. We obtained 315 blood or bone marrow samples from the National Donor Marrow Program Registry from children under age 18 with bone marrow failure who underwent an unrelated stem cell transplant. We screened these samples for mutations in the TERC gene using direct DNA sequencing. To exclude polymorphisms, we also screened 537 racially diverse healthy controls. The study group was composed of patients with MDS (n=151), AA (n=123), and juvenile myelomonocytic leukemia (JMML) (n=41), which may be difficult to distinguish from MDS. The mean age at the time of transplant was 9 years. We found sequence alterations in the promoter region of TERC in 2 patients. A 2 base pair deletion (-240delCT) was identified in a 4 year-old child with MDS and a 1 year-old child with JMML was found to have a point mutation (-99C→G), which was identified previously in an 18 year-old patient with paroxysmal nocturnal hemoglobinuria and is known to affect the Sp1 binding site. The pathogenicity of this mutation is unclear. In summary, our findings suggest that screening for TERC gene mutations is unlikely to diagnose occult DC in children with severe bone marrow failure who require a stem cell transplant but have no clinical features or history to suggest a familial bone marrow failure syndrome.

Telomerase Gene Mutation Screening and Telomere Length Detection in Chinese Patients with Bone Marrow Failure Syndrome.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1047-1047
Author(s):  
Bing Han ◽  
Bo Liu ◽  
Yongqiang Zhao
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Small Group ◽  
Telomere Length ◽  
Gene Mutation ◽  
Bone Marrow Failure ◽  
Chinese Patients ◽  
Chinese People ◽  
Bone Marrow Failure Syndrome ◽  
Tert Mutation

Abstract Background Acquired bone marrow failure syndrome (BMF) is a group of diseases include aplastic anemia(AA), melodysplastic syndrome (MDS) and paraoxymal nocturnal hemoglobinuria (PNH). Some BMF patients have short telomeres in their peripheral nucleated cells. The length of telomere is maintained by a group of enzymes called telomerase complex. The core components of this complex are a RNA template and a reverse transcriptase, called TERC and TERT, respectively. Recently several studies in the west and Japan have disclosed the presence of telomerase complex gene mutation in a small group of patients with acquired bone marrow failure. They speculated that this small group of patients might represent a subset of cryptogenic Dyskeratosis Congenita (DKC), in which the premature exhaustion of hematopoietic reservoir is caused by mutations in the telomerase gene. This group of patients, though very small in number, would benefit from early bone marrow transplantation instead of traditional immunosuppressive therapy. The incidence of aplastic anemia in Chinese people is relatively high compared with that in the western country. But there has so far been no study in China about the incidence of telomerase gene mutation in acquired bone marrow failure and its relationship with telomere length. Objectives To study the incidence of telomerase gene (namely TERC and TERT ) mutation in Chinese patients with acquired bone marrow failure and explore its relationship with telomere shortening. Methods Blood samples from 90 patients with AA, MDS, and PNH in northern China were collected and performed TERC and TERT mutation analysis. Telomere length was measured by Southern blotting and compared with their normal counterparts. Results 2 TERC mutations (n37 A→G, reported previously ; n66G→C) and 2 TERT mutations (n1870G→T (E/*); n1780G→T (S/I) ) were identified in 90 BMF patients. Among them, 3 mutations are reported first time. 1 patient with TERT mutation, however, was finally diagnosed as DKC instead of acquired AA, making the incidence of telomerase gene mutation in Chinese people with acquired bone marrow failure 3.4%, similar to that of the western people. Southern Blot analysis showed the small group of patients carrying TERC and TERT mutations has very short telomeres, compared with normal controls and with their aplastic counterparts. Conclusions The incidence of telomerase gene mutation in Chinese people with acquired bone marrow failure is 3.4%, similar to that of the western people. This small group of patients has very short telomeres, it is thus clinically important to screen for this small group of patients.

Identifying Unexpected Inherited Marrow Failure Syndromes in Adults Presenting with Aplastic Anemia, MDS or Solid Tumors

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5071-5071
Author(s):  
Curtis Lachowiez ◽  
Gabrielle Meyers
Keyword(s):  
Bone Marrow ◽  
Genetic Counseling ◽  
Aplastic Anemia ◽  
Solid Tumors ◽  
Early Recognition ◽  
Bone Marrow Failure ◽  
Family Members ◽  
Blood Dyscrasia ◽  
Solid Organ ◽  
Increased Risk

Abstract The inherited marrow failure syndromes, most importantly Fanconi Anemia (FA) and the Telomere Diseases, are associated not only with marrow failure, but with endocrinopathies, pulmonary fibrosis, cirrhosis and solid organ malignancies. While these disorders classically present in childhood with physical traits and blood count abnormalities, in reality, there is a wide spectrum of clinical findings in these syndromes. Patients may present with solid organ malignancies, pulmonary or liver abnormalities, aplastic anemia (AA) or myelodysplastic syndrome (MDS). Such presentations in adults require a high index of suspicion on behalf of the clinician during the initial stages of diagnosis, as prompt recognition of an inherited marrow failure disorder is imperative to creating an optimal treatment course. Early recognition allows for institution of surveillance programs for solid tumors, routine blood and bone marrow monitoring for the development of AA or MDS, and imparts a certain prognosis. It also allows for screening of additional family members (most important siblings who may be considered as bone marrow donors) and genetic counseling for families affected by these disorders. Treatment is often directed at the underlying bone marrow failure, and as highlighted by the recently published experience at the NIH (Townsley DM et al, NEJM 2016; 374), specific drugs may impact the disease trajectory. While FA and the other inherited marrow failure syndromes are thought of as primarily diseases of the young, patients can present at older ages. We have therefore established a screening program for patients presenting with MDS under the age of 60, AA patients under the age of 65, and head and neck cancers under the age of 60. Patients presenting with these findings are subject to screening with telomere length testing and blood breakage testing to screen for inherited marrow failure syndromes. With this testing approach, we have identified eight patients with unrecognized inherited bone marrow defects (see Table). Five patients met the criteria for a Telomere Disease, and three patients were diagnosed with FA. Of this subset of patients, only two (20%) had physical characteristics of an inherited bone marrow disorder. In these eight patients, the treatment approach was modulated significantly, including reducing conditioning for BMT, utilizing danazol as first line treatment for AA, and aggressive cancer/endocrinopathy screening. The importance of recognizing an inheritable syndrome cannot be understated. Treatment options for these patients vary widely compared to the standard approach for acquired MDS and AA. Family members of these patients need to be screened for defects if they are potential bone marrow donors, family members are potentially at increased risk for malignancy and marrow failure, and their offspring are at increased risk of inheritance of the mutated gene. Thus, patients and their family members should be engaged in genetic counselling and encouraged to pursue screening for the inherited marrow failure disorder. Affected individuals should then undergo a comprehensive surveillance program consisting of genetic counseling, and screening for associated endocrine, genitourinary, gastrointestinal, ophthalmologic and hematologic pathology in addition to screening for solid tumors. Thus, the approach to the congenital/inherited marrow failure syndromes is bimodal. For cases that present in childhood, early recognition can lead to institution of surveillance for malignancy, blood dyscrasia, and marrow failure as well as family counseling via a genetic specialist. Similarly, recognition of delayed presentations is equally paramount, as the adult who presents with MDS, AML, or aplastic anemia is still at increased risk for solid tumors and a more aggressive transformation to a hematologic malignancy. Additionally, identifying a family member with an inheritable condition allows for screening and surveillance of unaffected, or phenotypically silent relatives, with implications ranging from simple counseling and screening, to pre-emptive treatment. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical approach to marrow failure

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 329-337 ◽  
Author(s):  
Akiko Shimamura
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Medical Management ◽  
Bone Marrow Failure ◽  
Clinical History ◽  
Clinical Approach ◽  
Careful Attention ◽  
Bone Marrow Failure Syndrome ◽  
Bone Marrow Failure Syndromes ◽  
Molecular Pathophysiology

Abstract The treatment and medical management of aplastic anemia fundamentally differ between patients with inherited versus acquired marrow failure; however, the diagnosis of an inherited bone marrow failure syndrome is frequently obscure. Recent exciting advances in our understanding of the molecular pathophysiology of the inherited bone marrow failure syndromes have resulted in a profusion of new tests to aid in diagnosis. This in turn has raised questions regarding the appropriate choice of testing for the patient presenting with aplastic anemia. Important clues to the diagnosis of an inherited marrow failure syndrome may be gleaned from careful attention to the clinical history, physical exam, and laboratory workup.

A Pilot Study Of Rituximab In Patients With Moderate Aplastic Anemia, Diamond-Blackfan Anemia and Pure Red Cell Aplasia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2479-2479 ◽  
Author(s):  
Sabrina Martyr ◽  
Arun Balakumuran ◽  
Aldemar Montero ◽  
Cynthia E. Dunbar ◽  
Elizabeth M. Kang ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Aplastic Anemia ◽  
Reticulocyte Count ◽  
Bone Marrow Failure ◽  
Pure Red Cell Aplasia ◽  
Red Cell ◽  
Diamond Blackfan Anemia ◽  
Red Cell Aplasia ◽  
Bone Marrow Failure Syndromes

Abstract Background Pure red cell aplasia (PRCA), Diamond-Blackfan anemia (DBA) and moderate aplastic anemia (MAA) are all bone marrow failure syndromes that are immune-mediated or may respond to immunosuppressive therapies (IST). Anti-thymocyte globulin, cyclosporine and corticosteroids have been used with some success but have significant toxicities. The humanized monoclonal antibody to the interleukin-2 receptor on T cells, daclizumab, showed efficacy in MAA and PRCA patients with some patients achieving transfusion independence (Sloand et al, Haematologica 2010). However, this agent has since been withdrawn from the market. It is increasing recognized that the anti-CD20 chimeric monoclonal antibody, rituximab, may modulate T cell immunity in addition to its known depletion of B cells (Staci, Seminars in Hematology 2010). There are anecdotal case reports of rituximab, showing benefit in PRCA. Here, we summarize our experience using rituximab in PRCA, DBA and MAA. Design and Methods We enrolled 11 patients with PRCA (n = 7), DBA (n = 1), and MAA (n = 3) who had failed at least one prior immunosuppressive regimen to receive rituximab 375 mg/m2intravenous infusions weekly times 4 doses (NCT00229619). Responses were evaluated at 3, 6 and 12 months. Patients with MAA, DBA or PRCA were eligible for trial participation. MAA was defined as a hypocellular marrow without evidence of an underlying disease process and depression of at least two of three cell lines (an absolute neutrophil count (ANC) ≤ 1200/µL, a platelet count ≤ 70,000/µL, and a hemoglobin ≤ 8.5 g/dL or absolute reticulocyte count (ARC) ≤ 60, 000/µL in transfusion-dependent patients) but who do not fulfill criteria for severe aplastic anemia (i.e. bone marrow cellularity < 30% and depression of two of the three peripheral counts: ANC < 500/µL, a platelet count < 20,000/µL and an ARC < 60,000/µL). DBA and PRCA were defined as anemia, reticulocytopenia (ARC ≤ 50, 000/µL) and absent or decreased marrow erythroid precursors. Patients with Fanconi’s anemia, other congenital bone marrow failure syndromes, cytologic abnormalities indicating myelodysplasia or recent/ongoing parvovirus infection were excluded. Complete response (CR) was defined as return of blood counts to normal. Partial response (PR) for MAA was defined as improvement in two of the three depressed blood counts that qualified patient for participation. PR for DBA/PRCA was defined as an increase in hemoglobin by 1.5 g/dl of blood and or ARC ≥ 50,000/µL but not meeting criteria for normal counts. Results Overall, 5/11 (45%) patients responded to rituximab, all achieving PR. At 3 months, one patient with PRCA had responded. At 6 months, two additional patients responded (one with PRCA, one with MAA). At 12 months, an additional two responses were confirmed (one PRCA, one MAA). One PRCA patient lost his response between the 6 and 12 month endpoint. Among the three responding PRCA patients, the mean reticulocyte count at study initiation was 4400/µL; this increased to 54,000/µL at 6 months and further increased to 61,000/µL at 12 months (including patient who lost his response). The study was terminated early for poor accrual; many eligible patients received alternate treatments at home. Due to early study termination, the duration of responses for majority of the patients is unknown. Given the reports of daclizumab efficacy in these diseases, 90% of our patients were previously treated with daclizumab. Notably, 3 of the patients responding to rituximab had previously not responded to daclizumab. Safety The most common toxicity of rituximab observed was an infusion related reaction affecting (8/11) 73% of patients with the first infusion of rituximab. One patient developed serum sickness after the third cycle which precluded the administration of the last dose. An expected decrease in quantitative immunoglobulin levels was observed; at the 6 month evaluation there was an 11% decrease in IgG and IgA; a greater decrease (48%) was observed in IgM. Conclusions Rituximab is a viable treatment option in the armamentarium for patients with PRCA and MAA. Rituximab is safe, effective, and easily administered. Responses can be delayed to beyond 6 months therefore we suggest observation for at least 6 months after rituximab administration. Disclosures: Off Label Use: Rituximab is not FDA approved for the treatment of Pure Red Cell Aplasia, Diamond-Blackfan Anemia or Moderate Aplastic Anemia.

Treatment of Severe Aplastic Anemia with Porcine Anti-Human Lymphocyte Globulin

2020 ◽  
Vol 26 (22) ◽  
pp. 2661-2667
Author(s):  
Qi Lv ◽  
Zhang Huiqin ◽  
Xiao Na ◽  
Liu Chunyan ◽  
Shao Zonghong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
New Product ◽  
Therapeutic Effects ◽  
First Line ◽  
Bone Marrow Failure Syndrome ◽  
Hematopoietic Stem

Aplastic anemia (AA) is a bone marrow failure syndrome characterized by pancytopenia. Decreased numbers of hematopoietic stem cells and impaired bone marrow microenvironment caused by abnormal immune function describe the major pathogenesis of AA. Hematopoietic stem cell transplantation and immunesuppressive therapy are the first-line treatments for AA. Porcine anti-lymphocyte globulin (p-ALG) is a new product developed in China. Several studies have shown that p-ALG exhibited good therapeutic effects in AA.

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