High-dose cyclophosphamide for refractory autoimmune hemolytic anemia

Moyo, Victor; Smith, D. P.; Brodsky, Isadore; Crilley, Pamela; Jones, Richard J.; Brodsky, Robert A.

doi:10.1182/blood-2002-01-0087

Cited by 99 publications

(63 citation statements)

References 15 publications

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“…High-dose cyclophosphamide is a highly immunosuppressive agent that, in addition to its successful use as a treatment for aplastic anemia [9][10][11] and other severe refractory autoimmune diseases, 14,16,21,22 has proven efficacy in allogeneic BMT as both a conditioning regimen 23 and graft-versus-host disease prophylaxis. 24 Cyclophosphamide's unique metabolism is responsible for its immunosuppressive yet stem cell-sparing properties.…”

Section: Discussionmentioning

confidence: 99%

“…High-dose cyclophosphamide is highly immunosuppressive and has been used to successfully treat SAA [9][10][11][12][13] and other severe autoimmune diseases [14][15][16][17] in several small trials. A pilot study of 10 patients treated with high-dose cyclophosphamide demonstrated that this approach has the potential to cure SAA; 6 of these patients had between 9 and 19 years of follow-up at the time of publication in 1996, 9 and all 6 remain alive and disease free with normal blood counts out 21 to 31 years from initial therapy (R.A.B.…”

Section: Introductionmentioning

confidence: 99%

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High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up

Brodsky

Chen

Dorr³

et al. 2010

Blood

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105

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Severe aplastic anemia (SAA) is a lifethreatening bone marrow failure disorder that can be treated with bone marrow transplantation, immunosuppressive therapy, and high-dose cyclophosphamide. Here, we report long-term follow-up on 67 SAA patients (44 treatment-naive and 23 refractory) treated with high-dose cyclophosphamide. At 10 years, the overall actuarial survival was 88%, the response rate was 71% with the majority being complete, and the actuarial event-free survival was 58% in 44 treatmentnaive SAA patients. Patients with refractory SAA fared less well after high-dose cyclophosphamide therapy; at 10 years, overall actuarial survival, response, and actuarial event-free survival rates were 62%, 48%, and 27%, respectively. High-dose cyclophosphamide is highly effective therapy for severe aplastic anemia. Large randomized controlled trials will be necessary to establish how results of high-dose cyclophosphamide compare with either bone marrow transplantation or standard immunosuppressive regimens, such as antithymocyte globulin and cyclosporine. (Blood. 2010;

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up

Brodsky

Chen

Dorr³

et al. 2010

Blood

Self Cite

105

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“…67 Alemtuzumab, a humanized anti-CD52 monoclonal antibody, has been shown to be effective in small series of patients with idiopathic refractory AIHA, with an overall complete remission rate in 13 of 16, including 3 pediatric cases. 23,68,69 However, because of the high toxicity, it is considered a "last resort" option in severe idiopathic AIHA unresponsive to all previous treatments.…”

Section: "Last Option" Treatmentsmentioning

confidence: 99%

Treatment of autoimmune hemolytic anemias

2014

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Autoimmune hemolytic anemia (AIHA) is a relatively uncommon disorder caused by autoantibodies directed against self red blood cells. It can be idiopathic or secondary, and classified as warm, cold (cold hemagglutinin disease (CAD) and paroxysmal cold hemoglobinuria) or mixed, according to the thermal range of the autoantibody. AIHA may develop gradually, or have a fulminant onset with life-threatening anemia. The treatment of AIHA is still not evidence-based. The first-line therapy for warm AIHA are corticosteroids, which are effective in 70-85% of patients and should be slowly tapered over a time period of 6-12 months. For refractory/relapsed cases, the current sequence of second-line therapy is splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to 20%), rituximab (effective in approx. 80-90% of cases), and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Additional therapies are intravenous immunoglobulins, danazol, plasma-exchange, and alemtuzumab and high-dose cyclophosphamide as last resort option. As the experience with rituximab evolves, it is likely that this drug will be located at an earlier point in therapy of warm AIHA, before more toxic immunosuppressants, and in place of splenectomy in some cases. In CAD, rituximab is now recommended as first-line treatment. ABSTRACT Treatment of warm AIHAThe traditional treatment of AIHA includes corticosteroids, splenectomy and conventional immunosuppressive drugs. Over recent years, some new therapies have become available and there has been some evidence of success. These therapies are primarily used in patients who are not candidates for or fail to respond to splenectomy, those who relapse after splenectomy, and those who cannot maintain stable hemoglobin levels without unacceptably high doses of corticosteroids. First-line therapy CorticosteroidsThere is general agreement that corticosteroids represent the first-line treatment for patients with warm antibody type AIHA, albeit their use is based on experience rather than hard evidence. In fact, there is little published information on their effectiveness, 1,16,17 and this is not supported by clinical trials. Corticosteroids, usually prednisone, are given at the initial dose of 1.0-1.5 mg/kg/day for 1-3 weeks until hemoglobin levels greater than 10 g/dL are reached. Response occurs mainly during the second week, and if none or minimal improvement is observed in the third week, this therapy is assumed to be ineffective. After stabilization of hemoglobin, prednisone should be gradually and slowly tapered off at 10-15 mg weekly to a daily dose of 20-30 mg, then by 5 mg every 1-2 weeks until a dose of 15 mg, and subsequently by 2.5 mg every two weeks with the aim of withdrawing the drug. Although one might be tempted to discontinue steroids more rapidly, AIHA patients should be treated for a minimum of three or four months with low doses of prednisone (≤10 mg/day).1 In fact, patients receiving low doses of cortico...

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“…Por esta razão, além do Brasil (14)(15)(16)(17)(18)(21)(22) e da China (16,(38)(39)(40) , incluindo Hong-Kong (41) , outros países emergentes, como a Rússia (42) , a Hungria (43) , a Coréia do Sul (44) , a República Tcheca (45) e a Grécia (46) têm se dedicado crescentemente ao TCTH em DAI. Uma outra questão de grande importância nesta área, e ainda bastante controversa, se refere ao mecanismo de ação do transplante das células-tronco hematopoéticas nas DAI e o papel das CTH (n. o 1, Tabela 2). No transplante autó-logo, existem três explicações possíveis para este mecanismo de ação (47) : 1) efeito isolado da imunossupressão em altas doses na eliminação de linfócitos auto-reativos; neste caso, as CTH deveriam apenas prover suporte hematopoético após a imunossupressão em altas doses, reduzindo o período de pancitopenia pós-transplante; 2) as CTH poderiam restaurar a auto-tolerância a tecidos próprios, perdida na emergência DAI; ou 3) as CTH poderiam promover reparação tecidual por meio de transdiferenciação das CTH ou outras CT em células do tecido lesado pela DAI. A primeira hipótese é suportada pelo benefício clínico observado em pacientes submetidos a imunossupressão em altas doses (200 mg/kg de ciclofosfamida endovenosa) sem resgate com CTH (48)(49)(50) . Nesses pacientes, o tempo de pancitopenia foi superior ao observado quando se usa resgate de CTH (14-17 dias vs. 8-10 dias) e não ocorreram recaídas após um seguimento médio de 29 meses para LES, 15 meses para anemia hemolítica auto-imune e de 6 meses a 6 anos para miastenia gravis.…”

Section: Possíveis Respostas Estratégias De Investigação Referênciaunclassified

“…Entretanto, os marcadores celulares mais eficientes conhecidos, retrovirais, dificilmente terão seu uso permitido a curto prazo, em razão de recentes acidentes ocorridos em protocolos de terapia gênica (60) . Uma forma indireta e mais limitada de se estudar o efeito das células-tronco hematopoéticas na terapia das DAI seria por meio de protocolos randomizados comparando o TCTH com a imunossupressão em altas doses isoladas, sem infusão de CTH (48)(49)(50) . Esses estudos, entretanto, são difíceis de realizar em razão do período prolongado de neutropenia a que seria submetido o grupo controle (sem resgate hematopoético).…”

Section: Possíveis Respostas Estratégias De Investigação Referênciaunclassified