Late complications following treatment for severe aplastic anemia (SAA) with high-dose cyclophosphamide (Cy): follow-up of a randomized trial

Tisdale, John F.; Maciejewski, Jaroslaw P.; Núñez, Olga; Rosenfeld, Stephen J.; Young, Neal S.

doi:10.1182/blood-2002-02-0494

Cited by 55 publications

(32 citation statements)

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“…1 Some might argue that treatment success in selected cases of syngeneic transplant is, in fact, not due to the transplant but is only the result of the immunosuppressive conditioning and posttransplant immunosuppression; as we know, treatment of AA with high-dose cyclophosphamide has been a topic of debate in the past. 17,18 Though the inability to measure donor chimerism precludes proof of syngeneic engraftment, rapid neutrophil recovery, as well as lack of influence of ATG, are strong surrogate indicators of actual engraftment rather than response to immunosuppressive treatment, which usually occurs after several months. 3 Despite the widespread use of ATG, its role in pre-transplant conditioning is also not clear in the setting of matched sibling transplant, where a randomized study failed to confirm the positive effect on engraftment observed in a retrospective comparison.…”

Section: Discussionmentioning

confidence: 99%

Syngeneic transplantation in aplastic anemia: pre-transplant conditioning and peripheral blood are associated with improved engraftment: an observational study on behalf of the Severe Aplastic Anemia and Pediatric Diseases Working Parties of the European Group for Blood and Marrow Transplantation

et al. 2013

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ARTICLES haematologica | 2013; 98(11) Aplastic Anemia Aplastic anemia is usually treated with immunosuppression or allogeneic transplant, depending on patient and disease characteristics. Syngeneic transplant offers a rare treatment opportunity with minimal transplant-related mortality, and offers an insight into disease mechanisms. We present here a retrospective analysis of all syngeneic transplants for aplastic anemia reported to the European Group for Blood and Marrow Transplantation. Between 1976 and 2009, 88 patients received 113 transplants. Most transplants (n=85) were preceded by a conditioning regimen, 22 of these including anti-thymocyte globulin. About half of transplants with data available (39 of 86) were followed by posttransplant immunosuppression. Graft source was bone marrow in the majority of cases (n=77). Transplant practice changed over time with more transplants with conditioning and anti-thymocyte globulin as well as peripheral blood stem cells performed in later years. Ten year overall survival was 93% with 5 transplant-related deaths. Graft failure occurred in 32% of transplants. Risk of graft failure was significantly increased in transplants without conditioning, and with bone marrow as graft source. Lack of posttransplant immunosuppression also showed a trend towards increased risk of graft failure, while anti-thymocyte globulin did not have an influence. In summary, syngeneic transplant is associated with a significant risk of graft failure when no conditioning is given, but has an excellent long-term outcome. Furthermore, our comparatively large series enables us to recommend the use of pre-transplant conditioning rather than not and possibly to prefer peripheral blood as a stem cell source. Syngeneic transplantation in aplastic anemia

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Section: Discussionmentioning

confidence: 99%

Syngeneic transplantation in aplastic anemia: pre-transplant conditioning and peripheral blood are associated with improved engraftment: an observational study on behalf of the Severe Aplastic Anemia and Pediatric Diseases Working Parties of the European Group for Blood and Marrow Transplantation

et al. 2013

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“…81 However, cyclophosphamide was found to be excessively toxic because of fungal infections and deaths in a randomized study at NIH, and relapse and clonal evolution were observed. 82,83 Recently, long-term follow-up of SAA patients treated with high-dose cyclophosphamide showed that the cumulative incidence of invasive fungal infection was 21% in treatment-naive and 39% in refractory SAA. 84,85 These incidences of invasive fungal infections are higher than those observed with horse ATG and represent the major toxicity of the high-dose cyclophosphamide regimen.…”

Section: Immunosuppressive Therapymentioning

confidence: 99%

How I treat acquired aplastic anemia

Scheinberg

Young

2012

Blood

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367

333

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Survival in severe aplastic anemia (SAA) has markedly improved in the past 4 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive biologics and drugs, and supportive care. However, management of SAA patients remains challenging, both acutely in addressing the immediate consequences of pancytopenia and in the long term because of the disease's natural history and the consequences of therapy. Recent insights into pathophysiology have practical implications. We review key aspects of differential diagnosis, considerations in the choice of firstand second-line therapies, and the management of patients after immunosuppression, based on both a critical review of the recent literature and our large personal and research protocol experience of bone marrow failure in the Hematology Branch of the National Heart, Lung, and Blood Institute. (Blood. 2012;120(6): 1185-1196) IntroductionUntil the 1970s, severe aplastic anemia (SAA) was almost uniformly fatal, but in the early 21st century most patients can be effectively treated and can expect long-term survival. Nevertheless, making a diagnosis and selecting among treatment options are not straightforward, and both physicians and patients face serious decision points at the outset of their disease to years after its presentation. We summarize our approach to SAA, with recommendations based on decades of experience in the clinic as well as a critical review of the literature. Unfortunately, as a rare disease, there are few large trials of any kind and even fewer randomized controlled studies, which usually provide the best evidence to guide practice in the clinic. Pathophysiology as basis of diagnosis and treatmentThe pathophysiology responsible for marrow cell destruction and peripheral blood pancytopenia has itself been inferred from the results of treatment in humans, with substantial in vitro and animal model support. The reader is referred to more didactic textbook chapters and formal reviews on these topics. [1][2][3][4] The success of HSCT in restoring hematopoiesis in SAA patients implicated a deficiency of HSCs. Hematologic improvement after immunosuppressive therapy (IST), initially in the context of rejected allogeneic grafts and then in patients receiving only IST, implicated the immune system in destruction of marrow stem and progenitor cells. Immune-mediated marrow failure can be modeled in the mouse by the "runt" version of GVHD, with HSC depletion and hematopoietic failure induced by infusion of lymphocytes mismatched at major or minor histocompatibility loci. 5,6 Genetics influences both the immune response and its effects on the hematopoietic compartment. There are histocompatibility gene associations with SAA, 7 and some cytokine genes may be more readily activated in patients because of differences in their regulation, as suggested by polymorphisms in promoter regions. 8 An inability to repair telomeres and to maintain the marrow's regenerative capacity, resulting from mutations in the complex of genes responsible for tel...

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“…83,84 In contrast, an NIH randomized study was halted early due to the development of fungal infections and a much higher death rate in the cyclophosphamide arm, 85 and both relapse and cytogenetic evolution were observed. 86 The major toxicity of high-dose cyclophosphamide, prolonged neutropenia with concomitant susceptibility to infection, is now addressed by the Baltimore investigators by routine antimicrobial prophylaxis and prolonged G-CSF administration. Cyclophosphamide therapy does not eradicate PNH clones, and relapses now have been observed in Baltimore.…”

Section: Treatment Immunosuppressionmentioning

confidence: 99%

Current concepts in the pathophysiology and treatment of aplastic anemia

Young

Calado

Scheinberg

2006

Blood

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782

529

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Aplastic anemia, an unusual hematologic disease, is the paradigm of the human bone marrow failure syndromes. Almost universally fatal just a few decades ago, aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. The molecular basis of the aberrant immune response and deficiencies in hematopoietic cells is now being defined genetically; examples are telomere repair gene mutations in the target cells and dysregulated T-cell activation pathways. Immunosuppression with antithymocyte globulins and cyclosporine is effective at restoring blood-cell production in the majority of patients, but relapse and especially evolution of clonal hematologic diseases remain problematic. Allogeneic stem-cell transplant from histocompatible sibling donors is curative in the great majority of young patients with severe aplastic anemia; the major challenges are extending the ben- IntroductionMore than 25 years have passed since our first, highly speculative review of aplastic anemia; in that fortunately obscure publication, pathophysiology was addressed tentatively and immunosuppressive therapies hardly at all. The article did reflect both the dismal prospects for patients with the severe form of marrow failure and the formidable practical difficulties of experimentation in a rare disorder in which the cells of interest had disappeared. Aplastic anemia was considered heterogenous in origin and virtually impossible to study systematically. At the bedside, the clinical emphasis was the identification of a putative causal factorexposure to benzene or a culpable pharmaceutical-to allow classification in an otherwise doomed patient. As progenitor assays were developed, diverse factors could be held theoretically responsible for failure to form colonies in tissue culture, ranging from quantitative and qualitative defects in stem cells and blocks in differentiation to a lack of stroma support or inadequate cytokine production, or the effects of a chemical poison.In the intervening decades, our understanding of aplastic anemia has cohered around a unified immune mechanism of hematopoietic-cell destruction, which was inferred from but also has informed effective immunosuppressive therapies for the disease (Figure 1). Technical advances in cell biology, flow cytometry, molecular biology, and immunology have provided methods to measure numbers and function of very limited numbers of cells. As a result, we have a more unified and rational view of aplastic anemia's pathophysiology; the disease is understood in its relation to other related marrow failure syndromes; and in many important respects an unusual blood syndrome can model more common autoimmune diseases of other organ systems (Figure 2). Particularly satisfying is that aplastic anemia is now amenable to cure or amelioration in most patients, based both on high-quality clinical trials and mechanistic insights from the experiment...

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Late complications following treatment for severe aplastic anemia (SAA) with high-dose cyclophosphamide (Cy): follow-up of a randomized trial

Cited by 55 publications

References 14 publications

Syngeneic transplantation in aplastic anemia: pre-transplant conditioning and peripheral blood are associated with improved engraftment: an observational study on behalf of the Severe Aplastic Anemia and Pediatric Diseases Working Parties of the European Group for Blood and Marrow Transplantation

Syngeneic transplantation in aplastic anemia: pre-transplant conditioning and peripheral blood are associated with improved engraftment: an observational study on behalf of the Severe Aplastic Anemia and Pediatric Diseases Working Parties of the European Group for Blood and Marrow Transplantation

How I treat acquired aplastic anemia

Current concepts in the pathophysiology and treatment of aplastic anemia

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