Recovery from Aplastic Anemia after Treatment with Cyclophosphamide

Baran, Daniel T.; Griner, Paul F.; Klemperer, Martin R.

doi:10.1056/nejm197612302952708

Cited by 104 publications

(29 citation statements)

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“…80 This experience was expanded in the 1990s using higher doses (200 mg/kg total dose) at a single institution. Response rates were comparable with horse ATG, but with apparently fewer late events (relapse and clonal evolution) in historical comparison.…”

Section: Immunosuppressive Therapymentioning

confidence: 99%

How I treat acquired aplastic anemia

Scheinberg

Young

2012

Blood

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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Section: Immunosuppressive Therapymentioning

confidence: 99%

How I treat acquired aplastic anemia

Scheinberg

Young

2012

Blood

367

333

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“…Bone marrow transplant has given pro mising results [26], as has the use of immunosuppressors such as cyclophosphamide [4,19] or antilymphocyte globulin [12,25].…”

Section: Discussionmentioning

confidence: 99%

“…We may conclude that patients with se vere A.A. are candidates for a different type of therapy, such as bone marrow transplant if a compatible donor is available [26,27], or immunosuppressive treatment with cyclo phosphamide [4,19] or antilymphocyte globulin [12,25].…”

Section: Discussionmentioning

confidence: 99%

Use of Androgens in Acquired Aplastic Anaemia

Pizzuto¹,

Conte²,

Sinco³

et al. 1980

Acta Haematol

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124 adult patients with acquired aplastic anaemia (A.A.) were studied. 54 presented as severe A.A. (mean survival of the whole group, 2.7 months and in those who died, 2.5 months; mortality 88.8%) while 70 were mild (mean survival of the whole group, 27.2 months and in those who died, 22.7 months; mortality, 28.5%). Sixty-four did not live long enough to have adequate therapeutic trials or developed severe hepatic failure which made it impossible to continue treatment. The effectiveness of 78 therapeutic periods of treatment in the 60 evaluable cases was analyzed as to aetiology and severity. A response was obtained in 31 (40%), of which 24 were with oxymethalone; 17 showed improvement after 6 months of treatment. No conclusions could be drawn as to the effectiveness of methalone, cyclophosphamide and prednisone because of the limited number of treatments. In severe A.A. only one of 13 treatments was effective, whereas 30 of the 65 used in mild A.A. gave a response. Oxymethalone was used in 23 out of 41 (56%). The aetiology, sex and age appeared to have no influence on the response of the 60 patients analyzed. The only factor which appears useful for prognosis as to the effectiveness of treatment is the severity of the case.

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“…Shortly thereafter, reports of autologous hematopoietic reconstitution following allogeneic bone marrow transplantation for SAA appeared, suggesting that high-dose cyclophosphamide alone could restore normal hematopoiesis in aplastic anemia [24,25,26]. In 1976, a case report in the New England Journal of Medicine described a patient with SAA who was successfully treated with high-dose cyclophosphamide alone [27]. Despite the apparent success of high-dose cyclophosphamide in treating SAA, the approach received little attention for another two decades due, in part, to the improving results with allogeneic BMT and the emergence of antithymocyte globulin and cyclosporine as a treatment for SAA.…”

Section: High-dose Cyclophosphamide For Severe Aplastic Anemiamentioning

confidence: 99%

High Dose Cyclophosphamide Treatment for Autoimmune Disorders

Brodsky

2002

The Scientific World JOURNAL

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High-dose cyclophosphamide (200 mg/kg) was initially developed as a conditioning regimen for allogeneic bone marrow transplantation. Recently, high-dose cyclophosphamide without bone marrow transplantation has been employed as a method to induce durable treatment-free remissions in severe aplastic anemia and a variety of other severe autoimmune disorders. The premise underlying this approach is that high-dose cyclophosphamide is maximally immunosuppressive, but not myeloablative. Early hematopoietic stem cells are spared the cytotoxicity of cyclophosphamide because of their high levels of aldehyde dehydrogenase, an enzyme that confers resistance to the drug. Conversely, autoimmune effector cells (T cells, B cells, and NK cells) are exquisitely sensitive to high-dose cyclophosphamide because of their relatively low levels of aldehyde dehydrogenase. Intensive investigation is underway to determine which autoimmune disorders will most benefit and where in the natural history of these diseases to employ this rapidly developing therapy.KEY WORDS: high dose cyclophosphamide, autoimmune disease, aplastic anemia, autoimmune hemolytic anemia, bone marrow transplantation DOMAINS: autoimmunity, hematology, bone marrow failure, pharmacology, aplastic anemia, bone marrow transplantation.

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Recovery from Aplastic Anemia after Treatment with Cyclophosphamide

Cited by 104 publications

References 5 publications

How I treat acquired aplastic anemia

How I treat acquired aplastic anemia

Use of Androgens in Acquired Aplastic Anaemia

High Dose Cyclophosphamide Treatment for Autoimmune Disorders

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