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Sweet spot for cyclophosphamide: a balancing act
Comment
Severe aplastic anaemia is a rare but life-threatening disorder for which allogeneic haemopoietic stemcell transplant (HSCT) is a potential cure. In patients younger than 35 years and up to 50 years of age without substantial comorbidities with HLA-matched sibling donor, upfront HSCT is the recommended treatment. Healthy patients without a HLA-matched sibling donor are offered HSCT as a second-line treatment after failure of immunosuppressive therapy.1 Although 60–70% of patients respond to immunosuppressive therapy, blood counts return to normal only in a third of patients, and another third need long-term cyclosporin therapy and the risk of relapse of aplastic anaemia and clonal evolution to myelodysplastic syndromes occurs in a further third of patients. HSCT, however, offers an opportunity for longlasting haematological response and minimises the risk of relapse and reduces the likelihood of clonal evolution. The outcomes of HLA-matched unrelated donor HSCT for aplastic anaemia has steadily improved in the past decade.2 This improvement in the setting of HLA-matched unrelated donor has been largely attributed to optimisation of HLA typing and matching, progress in supportive care and prophylaxis of graftversus-host disease, incorporation of fludarabine in conditioning regimens, and the addition of low-dose total body irradiation. Additionally, the incorporation of alemtuzumab as a substitute to anti-thymocyte globulin in conditioning regimens has greatly improved transplant outcomes, especially in UK centres, with similar overall survival as with anti-thymocyte globulinbased conditioning but lower incidence of both acute and chronic graft-versus-host disease and better tolerance in patients with comorbidies.3,4 The expanded role of HLA-matched unrelated donor HSCT in the first-line setting has been successfully investigated in children and young adults with aplastic anaemia without a HLA-matched sibling donor using in-vivo T-cell depletion as part of the conditioning regimen.5 Cyclophosphamide, albeit at variable doses, forms the backbone for most, if not all, conditioning regimens for aplastic anaemia. In The Lancet Haematology Paolo Anderlini and colleagues6 aimed to de-escalate the dose of cyclophosphamide in a well-designed phase 1–2 study by the Blood and Marrow Transplant www.thelancet.com/haematology Vol 2 September 2015
Clinical Trials Network of unrelated donor HSCT. The regimen also included fludarabine (30 mg/m² per day), anti-thymocyte globulin (rabbit 3 mg/kg per day or horse 30 mg/kg per day for 3 days), and total body irradiation (2 Gy). Cyclophosphamide dosing started at 150 mg/kg for the cohorts in phase 1 and de-escalated in steps of 50 mg/kg depending on graft failure and death. The data from the initial cohorts that either omitted cyclophosphamide (n=3) or used doses of 150 mg/kg (n=14) resulted in universal graft failure or excess toxicity, respectively, as reported in 2012.7 Although the Bayesian dose-finding approach assigned cyclophosphamide 150 mg/kg as the desirable dose, this dose resulted in excess regimen-related toxicity with 50% mortality, so the subsequent 79 patients were accrued to 100 mg/kg (n=41) and 50 mg/kg (n=38) doses. In Anderlini and colleagues’ study, the median age of patients at transplantation was 20·6 years (range 0·5– 65·9) with a median follow-up of nearly 2 years. They report outcome data for cyclophosphamide 50 mg/kg and 100 mg/kg, with 1 year survival of 97·4% (95% CI 82·8–99·6) and 80·5% (64·8–89·7), graft failure 8% and 15%, and major regimen-related toxicity of 11% and 22%, respectively. HLA mismatches were more frequent in the 100 mg/kg cohort than in the 50 mg/kg cohort (34% vs 18%). The cumulative incidence of graft failure at 1 year was 11·7% (95% CI 3·5–25·4) and 14·6% (5·9–27·2) in the cyclophosphamide 50 mg/kg and 100 mg/kg cohorts, respectively, and, interestingly, all but one of these patients had secondary graft failure at about 2 months. The addition of fludarabine to a preparative conditioning regimen has been shown to facilitate engraftment and additionally the investigators of the current study hypothesise a cyclophosphamidesparing effect of fludarabine with lower regimen-related toxicity, based on in-vitro synergism data. Overall the investigators conclude that cyclophosphamide 50 mg/kg is the most desirable dose in combination with total body irradiation at a low dose, fludarabine, and anti-thymocyte globulin for unrelated-donor HSCT for aplastic anaemia, providing good engraftment, reduced non-haematological toxicity, and promising early survival data. The effect of cyclophosphamide is obviously greatly affected
Biophoto Associates/Science Photo Library
Sweet spot for cyclophosphamide: a balancing act
See Articles page e367
e350
Comment
by other agents in the preparative regimen because the dose of 1200 mg/m² (about 30 mg/kg) used with alemtuzumab in regimens in the UK resulted in graft failure of 14·5%, whereas the same dose in antithymocyte globulin-based conditioning resulted in 32% rejection in patients older than 16 years.8 The rejection was partly overcome with the addition of total body irradiation and increasing the cyclophosphamide dose to 120 mg/kg.9 Although there was variability in the preparation of anti-thymocyte globulin (horse or rabbit) used in conditioning, and additionally the two groups differed for HLA matching and recipient age, which might have affected the choice of the desirable dose—ie, 50 mg/kg cyclophosphamide, the investigators should be congratulated on designing and implementing this important prospective study for HSCT in a rare disease like severe aplastic anaemia.
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*Austin G Kulasekararaj, Judith C W Marsh Department of Haematological Medicine, Kings College Hospital and Kings College London, Denmark Hill, London SE5 9RS, UK (AGK, JCWM) [email protected] We declare no competing interests.
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Marsh JC, Ball SE, Cavenagh J, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol 2009; 147: 43–70. Bacigalupo A, Marsh JC. Unrelated donor search and unrelated donor transplantation in the adult aplastic anaemia patient aged 18-40 years without an HLA-identical sibling and failing immunosuppression. Bone Marrow transplant 2013; 48: 198–200. Marsh JC, Gupta V, Lim Z, et al. Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia. Blood 2011; 118: 2351–57. Samarasinghe S, Steward C, Hiwarkar P, et al. Excellent outcome of matched unrelated donor transplantation in paediatric aplastic anaemia following failure with immunosuppressive therapy: a United Kingdom multicentre retrospective experience. Br J Haematol 2012; 157: 339–46. Dufour C, Veys P, Carraro E, et al. Similar outcome of upfront-unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party, Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT. Br J Haematol 2015; published online July 28. DOI:10.1111/ bjh.13614. Anderlini P, Wu J, Gersten I, et al. Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1–2 dose de-escalation study. Lancet Haematol 2015; 2: e367–75. Tolar J, Deeg HJ, Arai S, et al. Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show lifethreatening adverse events at predefined cyclophosphamide dose levels. Biol Blood Marrow Transplant 2012; 18: 1007–11. Bacigalupo A, Locatelli F, Lanino E, et al. Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. Bone Marrow Transplant 2005; 36: 947–50. Bacigalupo A, Socie G, Lanino E, et al. Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA Working Party. Haematologica 2010; 95: 976–82.
www.thelancet.com/haematology Vol 2 September 2015
Severe aplastic anaemia is a rare but life-threatening disorder for which allogeneic haemopoietic stemcell transplant (HSCT) is a potential cure. In patients younger than 35 years and up to 50 years of age without substantial comorbidities with HLA-matched sibling donor, upfront HSCT is the recommended treatment. Healthy patients without a HLA-matched sibling donor are offered HSCT as a second-line treatment after failure of immunosuppressive therapy.1 Although 60–70% of patients respond to immunosuppressive therapy, blood counts return to normal only in a third of patients, and another third need long-term cyclosporin therapy and the risk of relapse of aplastic anaemia and clonal evolution to myelodysplastic syndromes occurs in a further third of patients. HSCT, however, offers an opportunity for longlasting haematological response and minimises the risk of relapse and reduces the likelihood of clonal evolution. The outcomes of HLA-matched unrelated donor HSCT for aplastic anaemia has steadily improved in the past decade.2 This improvement in the setting of HLA-matched unrelated donor has been largely attributed to optimisation of HLA typing and matching, progress in supportive care and prophylaxis of graftversus-host disease, incorporation of fludarabine in conditioning regimens, and the addition of low-dose total body irradiation. Additionally, the incorporation of alemtuzumab as a substitute to anti-thymocyte globulin in conditioning regimens has greatly improved transplant outcomes, especially in UK centres, with similar overall survival as with anti-thymocyte globulinbased conditioning but lower incidence of both acute and chronic graft-versus-host disease and better tolerance in patients with comorbidies.3,4 The expanded role of HLA-matched unrelated donor HSCT in the first-line setting has been successfully investigated in children and young adults with aplastic anaemia without a HLA-matched sibling donor using in-vivo T-cell depletion as part of the conditioning regimen.5 Cyclophosphamide, albeit at variable doses, forms the backbone for most, if not all, conditioning regimens for aplastic anaemia. In The Lancet Haematology Paolo Anderlini and colleagues6 aimed to de-escalate the dose of cyclophosphamide in a well-designed phase 1–2 study by the Blood and Marrow Transplant www.thelancet.com/haematology Vol 2 September 2015
Clinical Trials Network of unrelated donor HSCT. The regimen also included fludarabine (30 mg/m² per day), anti-thymocyte globulin (rabbit 3 mg/kg per day or horse 30 mg/kg per day for 3 days), and total body irradiation (2 Gy). Cyclophosphamide dosing started at 150 mg/kg for the cohorts in phase 1 and de-escalated in steps of 50 mg/kg depending on graft failure and death. The data from the initial cohorts that either omitted cyclophosphamide (n=3) or used doses of 150 mg/kg (n=14) resulted in universal graft failure or excess toxicity, respectively, as reported in 2012.7 Although the Bayesian dose-finding approach assigned cyclophosphamide 150 mg/kg as the desirable dose, this dose resulted in excess regimen-related toxicity with 50% mortality, so the subsequent 79 patients were accrued to 100 mg/kg (n=41) and 50 mg/kg (n=38) doses. In Anderlini and colleagues’ study, the median age of patients at transplantation was 20·6 years (range 0·5– 65·9) with a median follow-up of nearly 2 years. They report outcome data for cyclophosphamide 50 mg/kg and 100 mg/kg, with 1 year survival of 97·4% (95% CI 82·8–99·6) and 80·5% (64·8–89·7), graft failure 8% and 15%, and major regimen-related toxicity of 11% and 22%, respectively. HLA mismatches were more frequent in the 100 mg/kg cohort than in the 50 mg/kg cohort (34% vs 18%). The cumulative incidence of graft failure at 1 year was 11·7% (95% CI 3·5–25·4) and 14·6% (5·9–27·2) in the cyclophosphamide 50 mg/kg and 100 mg/kg cohorts, respectively, and, interestingly, all but one of these patients had secondary graft failure at about 2 months. The addition of fludarabine to a preparative conditioning regimen has been shown to facilitate engraftment and additionally the investigators of the current study hypothesise a cyclophosphamidesparing effect of fludarabine with lower regimen-related toxicity, based on in-vitro synergism data. Overall the investigators conclude that cyclophosphamide 50 mg/kg is the most desirable dose in combination with total body irradiation at a low dose, fludarabine, and anti-thymocyte globulin for unrelated-donor HSCT for aplastic anaemia, providing good engraftment, reduced non-haematological toxicity, and promising early survival data. The effect of cyclophosphamide is obviously greatly affected
Biophoto Associates/Science Photo Library
Sweet spot for cyclophosphamide: a balancing act
See Articles page e367
e350
Comment
by other agents in the preparative regimen because the dose of 1200 mg/m² (about 30 mg/kg) used with alemtuzumab in regimens in the UK resulted in graft failure of 14·5%, whereas the same dose in antithymocyte globulin-based conditioning resulted in 32% rejection in patients older than 16 years.8 The rejection was partly overcome with the addition of total body irradiation and increasing the cyclophosphamide dose to 120 mg/kg.9 Although there was variability in the preparation of anti-thymocyte globulin (horse or rabbit) used in conditioning, and additionally the two groups differed for HLA matching and recipient age, which might have affected the choice of the desirable dose—ie, 50 mg/kg cyclophosphamide, the investigators should be congratulated on designing and implementing this important prospective study for HSCT in a rare disease like severe aplastic anaemia.
1 2
3
4
5
6
7
8
*Austin G Kulasekararaj, Judith C W Marsh Department of Haematological Medicine, Kings College Hospital and Kings College London, Denmark Hill, London SE5 9RS, UK (AGK, JCWM) [email protected] We declare no competing interests.
e351
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Marsh JC, Ball SE, Cavenagh J, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol 2009; 147: 43–70. Bacigalupo A, Marsh JC. Unrelated donor search and unrelated donor transplantation in the adult aplastic anaemia patient aged 18-40 years without an HLA-identical sibling and failing immunosuppression. Bone Marrow transplant 2013; 48: 198–200. Marsh JC, Gupta V, Lim Z, et al. Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia. Blood 2011; 118: 2351–57. Samarasinghe S, Steward C, Hiwarkar P, et al. Excellent outcome of matched unrelated donor transplantation in paediatric aplastic anaemia following failure with immunosuppressive therapy: a United Kingdom multicentre retrospective experience. Br J Haematol 2012; 157: 339–46. Dufour C, Veys P, Carraro E, et al. Similar outcome of upfront-unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party, Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT. Br J Haematol 2015; published online July 28. DOI:10.1111/ bjh.13614. Anderlini P, Wu J, Gersten I, et al. Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1–2 dose de-escalation study. Lancet Haematol 2015; 2: e367–75. Tolar J, Deeg HJ, Arai S, et al. Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show lifethreatening adverse events at predefined cyclophosphamide dose levels. Biol Blood Marrow Transplant 2012; 18: 1007–11. Bacigalupo A, Locatelli F, Lanino E, et al. Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. Bone Marrow Transplant 2005; 36: 947–50. Bacigalupo A, Socie G, Lanino E, et al. Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA Working Party. Haematologica 2010; 95: 976–82.
www.thelancet.com/haematology Vol 2 September 2015