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Conditioning regimens for refractory acute myeloid leukaemia
Comment
Complete remission is the optimum disease state to pursue allogeneic haemopoietic cell transplantation (HCT) in patients with acute myeloid leukaemia. However, 20–50% of adults with acute myeloid leukaemia are not able to achieve complete remission with initial induction therapy, and less than 50% achieve complete remission after re-treatment at the time of relapse.1 Patients with active refractory or relapsed acute myeloid leukaemia are a therapeutic challenge and generally have very poor survival; however, allogeneic HCT using myeloablative conditioning regimens can lead to long-term remission in selected patients.2 Conditioning regimens in the early transplantation era were mainly based around total body irradiation (TBI). Concerns about toxic effects prompted attempts to switch to chemotherapy-only regimens. Results of randomised trials undertaken in the 1990s suggested a trend towards better disease-free survival with cyclophosphamide plus TBI than with busulfan plus cyclophosphamide.3 With advances in supportive care and an improved understanding of busulfan pharmacokinetics, similar or better outcomes with the busulfan plus cyclophosphamide regimen (using intravenous busulfan) have been reported in patients who have received HCT when in remission.4,5 However, cyclophosphamide plus TBI still tends to be preferred for patients with active refractory or relapsed acute myeloid leukaemia because of the perception that TBI might increase the possibility of disease control. Arnon Nagler and colleagues6 challenge this conventional wisdom with their study that used data from the European Group for Blood and Marrow Transplantation registry.6 They show that a cohort of 852 recipients of myeloablative HCT with refractory or relapsed acute myeloid leukaemia not in remission who received either intravenous busulfan plus cyclophosphamide (n=514) or cyclophosphamide plus TBI regimens (n=338) had similar overall survival, disease-free survival, and risk of relapse. In the multivariable analysis, patients in the cyclophosphamide plus TBI group had a marginally lower risk of nonrelapse mortality than did those in the busulfan plus cyclophosphamide group (hazard ratio [HR] 0·69 [95% CI 0·49–0·99]; p=0·04), but a lower probability of achieving complete remission (HR 1·39 [1·00–1·92]; www.thelancet.com/haematology Vol 2 September 2015
p=0·048). No differences were reported in the proportions of patients with graft-versus-host disease or hepatic veno-occlusive disease between groups. Use of non-TBI-based conditioning regimens for HCT is increasing, and these data should reassure clinicians that either myeloablative regimen can be used in these very high-risk patients. This finding is especially relevant for transplant centres that do not have the infrastructure to provide TBI. Nagler and colleagues’ study has several limitations that are inherent to a registry-based retrospective cohort study. Also, recipients of umbilical cord blood and haploidentical transplantation were excluded, both of which are fairly established alternative graft sources. Nonetheless, several important issues that will have an immediate effect on clinical practice should be mentioned. First, the results reaffirm that myeloablative HCT can lead to durable remission in a carefully selected subset of patients with refractory or relapsed acute myeloid leukaemia who are not in remission. The probability of 2 year survival was 31·2% (95% CI 26·8–35·5) in the intravenous busulfan plus cyclophosphamide recipients and 33·4% (28·1–38·7) in the cyclophosphamide plus TBI regimen recipients. Second, the findings show that even in patients with active leukaemia, earlier transplantation can lead to improved outcomes. Patients with primary refractory disease had better survival than patients in first relapse, who in turn had better survival than patients in second relapse. With the various graft sources now available, a suitable donor source can be identified for nearly all patients who might benefit from transplantation. Hence, patient HLA-typing should be done for all patients with acute myeloid leukaemia (with the exception of acute myeloid leukaemia with favourable cytogenetics) soon after starting therapy. If indicated, a donor search should also occur early, which will facilitate transplantation when it is appropriate for a given patient and will prevent delays that can occur when the donor search is initiated late in the disease course. In the meantime, more research is being done to better understand the biology of acute myeloid leukaemia that is not responsive to therapy and the role of novel agents, including cellular therapies, in their management.
J Bernard/Cnri/Science Photo Library
Conditioning regimens for refractory acute myeloid leukaemia
Published Online August 25, 2015 http://dx.doi.org/10.1016/ S2352-3026(15)00154-4 See Articles page e384
e354
Comment
In summary, patients with active refractory or relapsed acute myeloid leukaemia should ideally be treated on clinical trials. As an alternative, selected patients who are not able or unlikely to achieve complete remission with salvage chemotherapy could be considered for myeloablative HCT using either busulfan plus cyclophosphamide or cyclophosphamide plus TBI.
2
3
4
5
Navneet S Majhail Blood and Marrow Transplant Program, Cleveland Clinic, Cleveland, OH 44195, USA [email protected] I declare no competing interests. 1
e355
Burnett AK, Goldstone A, Hills RK, et al. Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission. J Clin Oncol 2013; 31: 1293–301.
6
Duval M, Klein JP, He W, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol 2010; 28: 3730–38. Socie G, Clift RA, Blaise D, et al. Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies. Blood 2001; 98: 3569–74. Copelan EA, Hamilton BK, Avalos B, et al. Better leukemia-free and overall survival in acute myeloid leukaemia in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood 2013; 122: 3863–70. Nagler A, Rocha V, Labopin M, et al. Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen—a report from the acute leukemia working party of the European group for blood and marrow transplantation. J Clin Oncol 2013; 31: 3549–56. Nagler A, Savani BN, Labopin M, et al. Outcomes after use of two standard ablative regimens in patients with refractory acute myeloid leukaemia: a retrospective, multicentre, registry analysis. Lancet Haematol 2015; published online Aug 25. http://dx.doi.org/10.1016/S23523026(15)00146-5.
www.thelancet.com/haematology Vol 2 September 2015
Complete remission is the optimum disease state to pursue allogeneic haemopoietic cell transplantation (HCT) in patients with acute myeloid leukaemia. However, 20–50% of adults with acute myeloid leukaemia are not able to achieve complete remission with initial induction therapy, and less than 50% achieve complete remission after re-treatment at the time of relapse.1 Patients with active refractory or relapsed acute myeloid leukaemia are a therapeutic challenge and generally have very poor survival; however, allogeneic HCT using myeloablative conditioning regimens can lead to long-term remission in selected patients.2 Conditioning regimens in the early transplantation era were mainly based around total body irradiation (TBI). Concerns about toxic effects prompted attempts to switch to chemotherapy-only regimens. Results of randomised trials undertaken in the 1990s suggested a trend towards better disease-free survival with cyclophosphamide plus TBI than with busulfan plus cyclophosphamide.3 With advances in supportive care and an improved understanding of busulfan pharmacokinetics, similar or better outcomes with the busulfan plus cyclophosphamide regimen (using intravenous busulfan) have been reported in patients who have received HCT when in remission.4,5 However, cyclophosphamide plus TBI still tends to be preferred for patients with active refractory or relapsed acute myeloid leukaemia because of the perception that TBI might increase the possibility of disease control. Arnon Nagler and colleagues6 challenge this conventional wisdom with their study that used data from the European Group for Blood and Marrow Transplantation registry.6 They show that a cohort of 852 recipients of myeloablative HCT with refractory or relapsed acute myeloid leukaemia not in remission who received either intravenous busulfan plus cyclophosphamide (n=514) or cyclophosphamide plus TBI regimens (n=338) had similar overall survival, disease-free survival, and risk of relapse. In the multivariable analysis, patients in the cyclophosphamide plus TBI group had a marginally lower risk of nonrelapse mortality than did those in the busulfan plus cyclophosphamide group (hazard ratio [HR] 0·69 [95% CI 0·49–0·99]; p=0·04), but a lower probability of achieving complete remission (HR 1·39 [1·00–1·92]; www.thelancet.com/haematology Vol 2 September 2015
p=0·048). No differences were reported in the proportions of patients with graft-versus-host disease or hepatic veno-occlusive disease between groups. Use of non-TBI-based conditioning regimens for HCT is increasing, and these data should reassure clinicians that either myeloablative regimen can be used in these very high-risk patients. This finding is especially relevant for transplant centres that do not have the infrastructure to provide TBI. Nagler and colleagues’ study has several limitations that are inherent to a registry-based retrospective cohort study. Also, recipients of umbilical cord blood and haploidentical transplantation were excluded, both of which are fairly established alternative graft sources. Nonetheless, several important issues that will have an immediate effect on clinical practice should be mentioned. First, the results reaffirm that myeloablative HCT can lead to durable remission in a carefully selected subset of patients with refractory or relapsed acute myeloid leukaemia who are not in remission. The probability of 2 year survival was 31·2% (95% CI 26·8–35·5) in the intravenous busulfan plus cyclophosphamide recipients and 33·4% (28·1–38·7) in the cyclophosphamide plus TBI regimen recipients. Second, the findings show that even in patients with active leukaemia, earlier transplantation can lead to improved outcomes. Patients with primary refractory disease had better survival than patients in first relapse, who in turn had better survival than patients in second relapse. With the various graft sources now available, a suitable donor source can be identified for nearly all patients who might benefit from transplantation. Hence, patient HLA-typing should be done for all patients with acute myeloid leukaemia (with the exception of acute myeloid leukaemia with favourable cytogenetics) soon after starting therapy. If indicated, a donor search should also occur early, which will facilitate transplantation when it is appropriate for a given patient and will prevent delays that can occur when the donor search is initiated late in the disease course. In the meantime, more research is being done to better understand the biology of acute myeloid leukaemia that is not responsive to therapy and the role of novel agents, including cellular therapies, in their management.
J Bernard/Cnri/Science Photo Library
Conditioning regimens for refractory acute myeloid leukaemia
Published Online August 25, 2015 http://dx.doi.org/10.1016/ S2352-3026(15)00154-4 See Articles page e384
e354
Comment
In summary, patients with active refractory or relapsed acute myeloid leukaemia should ideally be treated on clinical trials. As an alternative, selected patients who are not able or unlikely to achieve complete remission with salvage chemotherapy could be considered for myeloablative HCT using either busulfan plus cyclophosphamide or cyclophosphamide plus TBI.
2
3
4
5
Navneet S Majhail Blood and Marrow Transplant Program, Cleveland Clinic, Cleveland, OH 44195, USA [email protected] I declare no competing interests. 1
e355
Burnett AK, Goldstone A, Hills RK, et al. Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission. J Clin Oncol 2013; 31: 1293–301.
6
Duval M, Klein JP, He W, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol 2010; 28: 3730–38. Socie G, Clift RA, Blaise D, et al. Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies. Blood 2001; 98: 3569–74. Copelan EA, Hamilton BK, Avalos B, et al. Better leukemia-free and overall survival in acute myeloid leukaemia in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood 2013; 122: 3863–70. Nagler A, Rocha V, Labopin M, et al. Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen—a report from the acute leukemia working party of the European group for blood and marrow transplantation. J Clin Oncol 2013; 31: 3549–56. Nagler A, Savani BN, Labopin M, et al. Outcomes after use of two standard ablative regimens in patients with refractory acute myeloid leukaemia: a retrospective, multicentre, registry analysis. Lancet Haematol 2015; published online Aug 25. http://dx.doi.org/10.1016/S23523026(15)00146-5.
www.thelancet.com/haematology Vol 2 September 2015