Leukemia (2015), 1–2 © 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15 www.nature.com/leu
COMMENTARY
To RIC or not to RIC: that is the question M Mohty1,2,3 and F Malard1,2,3 Leukemia advance online publication, 14 April 2015; doi:10.1038/leu.2015.82 In this issue of the journal, Russell et al.1 reports on the MRC's AML15 trial results evaluating whether a matched sibling (SIB) or unrelated donor (MUD) allogeneic stem cell transplantation (allo-SCT) for acute myeloid leukemia (AML) compared favorably with chemotherapy consolidation in 1st remission at intermediate or high risk of relapse. Some transplant recipients received conventional, standard myeloablative high-dose pre-transplant conditioning (MAC) and other reduced-intensity conditioning (RIC). The choice of whether to do a transplant and which pre-transplant conditioning regimen use was left to the physician’s choice. Moreover, not all subjects meant to receive a transplant of either type did so. Also, the study relied mainly on conventional cytogenetic analysis which may not be the most appropriate approach for risk assessment at the era of molecular biology and next-generation sequencing. These issues, of course, confound any critical analyses of the outcomes. Moreover, the sophisticated multiple statistical comparisons which did not attempt to include an ‘intent-to-treat’ analysis made the overall interpretation of results quite difficult. Nevertheless, in this study it appeared that the use of RIC prior to allo-SCT significantly reduced relapse incidence and the 5-year overall survival from a SIB donor RIC allo-SCT was superior to RIC allo-SCT from a MUD owing to lower non-relapse mortality (NRM). Also, there was a survival benefit for RIC allo-SCT from a SIB donor over chemotherapy. Focusing on the age 35–44 group, patients given RIC allo-SCT enjoyed better outcomes compared with patients who received standard MAC allo-SCT. In the last 15 years, the so-called non-myeloablative or RIC regimens for allo-SCT have emerged as an attractive modality to decrease allo-SCT-related toxicities and NRM.2,3 Indeed, RIC allo-SCT represents an attempt to harness the immune graftversus-tumor effect while attempting to control or overcome toxicity.4 The work of different pioneering groups rapidly proved that this approach is feasible in several disease settings or patient categories,5,6 and had the added benefit of expanding the transplant option to elderly patients who are ineligible for standard MAC allo-SCT. From a clinical standpoint, it is now well established that the use of such RIC regimens is associated with decreased short-term toxicity and organ damage after allo-SCT.7 Unfortunately, and despite several thousands of patients receiving RIC allo-SCT reported to international registries, the true value of RIC allo-SCT in the management of AML was, as yet, difficult to delineate. Although the positive impact of RIC allo-SCT in terms of NRM reduction has been well established, the putative higher incidence of disease relapse after RIC allo-SCT has been a major mater of concern.8 Therefore, many investigators were not keen to propose RIC allo-SCT strategies for those patients who could tolerate a standard MAC. Moreover, until recently, there were only very few, if any, prospective, randomized or controlled trials that
have addressed the specific role of RIC allo-SCT in net health outcomes that should include, in a specific disease setting such as AML, an analysis of disease-free survival and overall survival balanced against treatment-related toxicity, complications and death. With this background, Russell et al.1 should be commended for performing such an important prospective trial. As a matter of fact, and as expected in this type of approach, the study suffers from a certain number of limitations. Beside the primary end point of the study, the authors performed some exploratory and secondary end points comparisons which should be handled cautiously. The analysis and conclusions related to allo-SCT using MUDs are difficult to interpret. Patients were recommended to receive allo-SCT from a MUD only if they had high-risk disease and thus have a higher risk of relapse and NRM (compared with the SIB donors group). Also, because the MUDs group could have a one antigen HLA mismatch, a higher risk of NRM would be expected compared with allo-SCT from a matched related sibling. Thus, a substantially higher NRM in the MUDs group could have confounded some of the analyses. In addition, the study design does not allow to have a precise picture on how many patients with a confirmed matched donor did not receive allo-SCT due to poor health status, medical condition. The latter can introduce a potential selection bias that is not easy to overcome in real life practice. Also, one must acknowledge that the so-called RIC preparative regimens were heterogeneous and may not have been equally effective in different centers (center effect?). The latter issue could not be addressed in this analysis. Despite the above limitations, and though one should bear in mind that this study was designed more than 10 years, the results of Russell and colleagues are still quite convincing.1 These results will definitely encourage investigators to reconsider some sort of ‘common belief’ attitude discouraging the use of RIC regimens in young patients. Also, they will pave the way for additional prospective research in this field. One important and more recent issue pertinent to the use of RIC regimens relates to the ‘intensity’ of the regimen. This issue could not be addressed in this study where the choice of the RIC regimen was left to the center’s choice.1 Because some analyses have suggested some differences between the truly nonmyeloablative RIC regimens (e.g., low dose TBI-based RIC)5 and other ‘intermediate’ intensity RIC regimens (e.g., Fludarabine and IV busulfan with doses ranging from 6.4 to 12.8 mg/kg total dose),6,9 it will be crucial in future studies to characterize the potency of such ‘less’ reduced RIC regimens in controlling the disease relapse, while waiting for the allogeneic immune graftversus-leukemia effect. Indeed, the field is currently moving from the concept of RIC to a more attractive concept called ‘reducedtoxicity conditioning’ (RTC). The use of such RTC regimens which might include fully myeloablative doses of cytoreductive agents, proved to be feasible even in frail patients with high-riskmalignancies.10 Indeed, one must acknowledge that AML encompasses a group of chemosensitive diseases, raising
1 Department of Hematology, Saint Antoine Hospital, Paris, France; 2INSERM UMR 938, Paris, France and 3Université Pierre et Marie Curie, Paris, France. Correspondence: Professor M Mohty, Department of Hematology, Hopital Saint Antoine, 184 rue du Faubourg Saint Antoine, Paris 75571, France. E-mail: [email protected]
Commentary
2 concerns that significant reduction in the intensity of the preparative regimen may have a negative impact on long-term disease control. Thus, investigators are always faced with a dilemma on how to decrease relapse after RIC allo-SCT, while minimizing NRM, and the optimal dose of cytoreductive drugs remains uncertain. The development of cytoreductive agents with an optimized tolerance profile (e.g., IV busulfan) will probably allow to increase the intensity of myeloablation delivered as part of a RIC regimen (RTC concept) and subsequently decrease the relapse rate, without increasing NRM.11 At present, the use of RIC prior to allo-SCT appears to be on the cutting-edge of transplantation research. The RIC/RTC approach is proving to be far more complex than originally thought. As the first reports published in the late 90s, hundreds of scientists and clinicians have joined together in furthering the use of these regimens. The complexity of RIC/RTC allo-SCT practice is progressively being deciphered and the optimism in regarding RIC allo-SCT as a potential and promising treatment modality for many patients remains very high among investigators, warranting continuous and renewed clinical and therapeutic research in this area. In our most recent single center analysis of the 2001–2010 decade, compared with the 1983–1990 and 1991–2000 decades, we observed a significant decrease in NRM and an increase in overall survival after allo-SCT mainly related to the use of RIC regimens despite the fact that older and higher risk patients with more comorbidities underwent transplantation in the last 10 years.12 Thus, we feel time has come to perform randomized controlled trials in comparable groups of patients (especially the younger ones) in order to assess whether MAC and RIC allo-SCT have comparable or different long-term outcomes. Although we value the accompanying comments from Dr RP Gale, these comments reminded us of sir AC Clarke (British science fiction writer) when he wrote ‘I don't believe in astrology; I'm a Sagittarius and we're skeptical.’ But, one must acknowledge that ‘even the Lord had skeptical members of his party: one betrayed him, one denied him and one doubted him’ (RJ Daley, American politician). Overall, we deeply believe that the study by Russell and colleagues1 is a further and important step in the right direction. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS FM was supported by an educational grant from the ‘Association for Training, Education and Research in Hematology, Immunology and Transplantation’ (ATERHIT). We thank the ‘Association pour la Recherche sur le Cancer (ARC), the ‘Fondation de France’, the ‘Fondation contre la Leucémie’, the ‘Agence de Biomédecine’, the ‘Association Cent pour Sang la Vie’, the ‘Association Laurette Fuguain’, the ‘International Research Group on Unrelated Hematopoietic Stem cell Transplantation’ and the ‘Ligue contre le Cancer (Comités Départementaux de l’Inter région Grand-
Leukemia (2015) 1 – 2
Ouest Bretagne, Centre, Pays-de-Loire, Poitou-Charentes)’, for their generous and continuous support for our clinical and basic research work. Our group is supported by several grants from the (Hospital Clinical Research Program from the French national cancer institute to MM).
REFERENCES 1 Russell N, Kjeldsen L, Craddock C, Pagliuca A, Yin J, Clark R et al. A comparative assessment of the curative potential of reduced intensity allografts in acute myeloid leukaemia. Leukemia 2014; e-pub ahead of print 7 November 2014; doi:10.1038/leu.2014.319. 2 Mohty M, de Lavallade H, El-Cheikh J, Ladaique P, Faucher C, Furst S et al. Reduced intensity conditioning allogeneic stem cell transplantation for patients with acute myeloid leukemia: long term results of a 'donor' versus 'no donor' comparison. Leukemia 2009; 23: 194–196. 3 Versluis J, Labopin M, Niederwieser D, Socie G, Schlenk RF, Milpied N et al. Prediction of non-relapse mortality in recipients of reduced intensity conditioning allogeneic stem cell transplantation with AML in first complete remission. Leukemia 2014; 29: 51–57. 4 Baron F, Labopin M, Niederwieser D, Vigouroux S, Cornelissen JJ, Malm C et al. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation. Leukemia 2012; 26: 2462–2468. 5 McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400. 6 Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763. 7 Mohty M, Apperley JF.. Long-term physiological side effects after allogeneic bone marrow transplantation. Hematology Am Soc Hematol Educ Program 2010; 2010: 229–236. 8 Mengarelli A, Iori A, Guglielmi C, Romano A, Cerretti R, Torromeo C et al. Standard versus alternative myeloablative conditioning regimens in allogeneic hematopoietic stem cell transplantation for high-risk acute leukemia. Haematologica 2002; 87: 52–58. 9 Kharfan-Dabaja MA, Labopin M, Bazarbachi A, Hamladji RM, Blaise D, Socie G et al. Comparing i.v. BU dose intensity between two regimens (FB2 vs FB4) for allogeneic HCT for AML in CR1: a report from the Acute Leukemia Working Party of EBMT. Bone Marrow Transplant 2014; 49: 1170–1175. 10 Mohty M, Malard F, Blaise D, Milpied N, Furst S, Tabrizi R et al. Reduced-toxicity conditioning with fludarabine, once-daily intravenous busulfan, and antithymocyte globulins prior to allogeneic stem cell transplantation: results of a multicenter prospective phase 2 trial. Cancer 2014; 121: 562–569. 11 Mohty M, Malard F, Savani BN.. High-dose total body irradiation and myeloablative conditioning before allogeneic stem cell transplantation: time to rethink? Biol Blood Marrow Transplant 2014; 21: 620–624. 12 Malard F, Chevallier P, Guillaume T, Delaunay J, Rialland F, Harousseau JL et al. Continuous reduced nonrelapse mortality after allogeneic hematopoietic stem cell transplantation: a single-institution's three decade experience. Biol Blood Marrow Transplant 2014; 20: 1217–1223.
© 2015 Macmillan Publishers Limited
COMMENTARY
To RIC or not to RIC: that is the question M Mohty1,2,3 and F Malard1,2,3 Leukemia advance online publication, 14 April 2015; doi:10.1038/leu.2015.82 In this issue of the journal, Russell et al.1 reports on the MRC's AML15 trial results evaluating whether a matched sibling (SIB) or unrelated donor (MUD) allogeneic stem cell transplantation (allo-SCT) for acute myeloid leukemia (AML) compared favorably with chemotherapy consolidation in 1st remission at intermediate or high risk of relapse. Some transplant recipients received conventional, standard myeloablative high-dose pre-transplant conditioning (MAC) and other reduced-intensity conditioning (RIC). The choice of whether to do a transplant and which pre-transplant conditioning regimen use was left to the physician’s choice. Moreover, not all subjects meant to receive a transplant of either type did so. Also, the study relied mainly on conventional cytogenetic analysis which may not be the most appropriate approach for risk assessment at the era of molecular biology and next-generation sequencing. These issues, of course, confound any critical analyses of the outcomes. Moreover, the sophisticated multiple statistical comparisons which did not attempt to include an ‘intent-to-treat’ analysis made the overall interpretation of results quite difficult. Nevertheless, in this study it appeared that the use of RIC prior to allo-SCT significantly reduced relapse incidence and the 5-year overall survival from a SIB donor RIC allo-SCT was superior to RIC allo-SCT from a MUD owing to lower non-relapse mortality (NRM). Also, there was a survival benefit for RIC allo-SCT from a SIB donor over chemotherapy. Focusing on the age 35–44 group, patients given RIC allo-SCT enjoyed better outcomes compared with patients who received standard MAC allo-SCT. In the last 15 years, the so-called non-myeloablative or RIC regimens for allo-SCT have emerged as an attractive modality to decrease allo-SCT-related toxicities and NRM.2,3 Indeed, RIC allo-SCT represents an attempt to harness the immune graftversus-tumor effect while attempting to control or overcome toxicity.4 The work of different pioneering groups rapidly proved that this approach is feasible in several disease settings or patient categories,5,6 and had the added benefit of expanding the transplant option to elderly patients who are ineligible for standard MAC allo-SCT. From a clinical standpoint, it is now well established that the use of such RIC regimens is associated with decreased short-term toxicity and organ damage after allo-SCT.7 Unfortunately, and despite several thousands of patients receiving RIC allo-SCT reported to international registries, the true value of RIC allo-SCT in the management of AML was, as yet, difficult to delineate. Although the positive impact of RIC allo-SCT in terms of NRM reduction has been well established, the putative higher incidence of disease relapse after RIC allo-SCT has been a major mater of concern.8 Therefore, many investigators were not keen to propose RIC allo-SCT strategies for those patients who could tolerate a standard MAC. Moreover, until recently, there were only very few, if any, prospective, randomized or controlled trials that
have addressed the specific role of RIC allo-SCT in net health outcomes that should include, in a specific disease setting such as AML, an analysis of disease-free survival and overall survival balanced against treatment-related toxicity, complications and death. With this background, Russell et al.1 should be commended for performing such an important prospective trial. As a matter of fact, and as expected in this type of approach, the study suffers from a certain number of limitations. Beside the primary end point of the study, the authors performed some exploratory and secondary end points comparisons which should be handled cautiously. The analysis and conclusions related to allo-SCT using MUDs are difficult to interpret. Patients were recommended to receive allo-SCT from a MUD only if they had high-risk disease and thus have a higher risk of relapse and NRM (compared with the SIB donors group). Also, because the MUDs group could have a one antigen HLA mismatch, a higher risk of NRM would be expected compared with allo-SCT from a matched related sibling. Thus, a substantially higher NRM in the MUDs group could have confounded some of the analyses. In addition, the study design does not allow to have a precise picture on how many patients with a confirmed matched donor did not receive allo-SCT due to poor health status, medical condition. The latter can introduce a potential selection bias that is not easy to overcome in real life practice. Also, one must acknowledge that the so-called RIC preparative regimens were heterogeneous and may not have been equally effective in different centers (center effect?). The latter issue could not be addressed in this analysis. Despite the above limitations, and though one should bear in mind that this study was designed more than 10 years, the results of Russell and colleagues are still quite convincing.1 These results will definitely encourage investigators to reconsider some sort of ‘common belief’ attitude discouraging the use of RIC regimens in young patients. Also, they will pave the way for additional prospective research in this field. One important and more recent issue pertinent to the use of RIC regimens relates to the ‘intensity’ of the regimen. This issue could not be addressed in this study where the choice of the RIC regimen was left to the center’s choice.1 Because some analyses have suggested some differences between the truly nonmyeloablative RIC regimens (e.g., low dose TBI-based RIC)5 and other ‘intermediate’ intensity RIC regimens (e.g., Fludarabine and IV busulfan with doses ranging from 6.4 to 12.8 mg/kg total dose),6,9 it will be crucial in future studies to characterize the potency of such ‘less’ reduced RIC regimens in controlling the disease relapse, while waiting for the allogeneic immune graftversus-leukemia effect. Indeed, the field is currently moving from the concept of RIC to a more attractive concept called ‘reducedtoxicity conditioning’ (RTC). The use of such RTC regimens which might include fully myeloablative doses of cytoreductive agents, proved to be feasible even in frail patients with high-riskmalignancies.10 Indeed, one must acknowledge that AML encompasses a group of chemosensitive diseases, raising
1 Department of Hematology, Saint Antoine Hospital, Paris, France; 2INSERM UMR 938, Paris, France and 3Université Pierre et Marie Curie, Paris, France. Correspondence: Professor M Mohty, Department of Hematology, Hopital Saint Antoine, 184 rue du Faubourg Saint Antoine, Paris 75571, France. E-mail: [email protected]
Commentary
2 concerns that significant reduction in the intensity of the preparative regimen may have a negative impact on long-term disease control. Thus, investigators are always faced with a dilemma on how to decrease relapse after RIC allo-SCT, while minimizing NRM, and the optimal dose of cytoreductive drugs remains uncertain. The development of cytoreductive agents with an optimized tolerance profile (e.g., IV busulfan) will probably allow to increase the intensity of myeloablation delivered as part of a RIC regimen (RTC concept) and subsequently decrease the relapse rate, without increasing NRM.11 At present, the use of RIC prior to allo-SCT appears to be on the cutting-edge of transplantation research. The RIC/RTC approach is proving to be far more complex than originally thought. As the first reports published in the late 90s, hundreds of scientists and clinicians have joined together in furthering the use of these regimens. The complexity of RIC/RTC allo-SCT practice is progressively being deciphered and the optimism in regarding RIC allo-SCT as a potential and promising treatment modality for many patients remains very high among investigators, warranting continuous and renewed clinical and therapeutic research in this area. In our most recent single center analysis of the 2001–2010 decade, compared with the 1983–1990 and 1991–2000 decades, we observed a significant decrease in NRM and an increase in overall survival after allo-SCT mainly related to the use of RIC regimens despite the fact that older and higher risk patients with more comorbidities underwent transplantation in the last 10 years.12 Thus, we feel time has come to perform randomized controlled trials in comparable groups of patients (especially the younger ones) in order to assess whether MAC and RIC allo-SCT have comparable or different long-term outcomes. Although we value the accompanying comments from Dr RP Gale, these comments reminded us of sir AC Clarke (British science fiction writer) when he wrote ‘I don't believe in astrology; I'm a Sagittarius and we're skeptical.’ But, one must acknowledge that ‘even the Lord had skeptical members of his party: one betrayed him, one denied him and one doubted him’ (RJ Daley, American politician). Overall, we deeply believe that the study by Russell and colleagues1 is a further and important step in the right direction. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS FM was supported by an educational grant from the ‘Association for Training, Education and Research in Hematology, Immunology and Transplantation’ (ATERHIT). We thank the ‘Association pour la Recherche sur le Cancer (ARC), the ‘Fondation de France’, the ‘Fondation contre la Leucémie’, the ‘Agence de Biomédecine’, the ‘Association Cent pour Sang la Vie’, the ‘Association Laurette Fuguain’, the ‘International Research Group on Unrelated Hematopoietic Stem cell Transplantation’ and the ‘Ligue contre le Cancer (Comités Départementaux de l’Inter région Grand-
Leukemia (2015) 1 – 2
Ouest Bretagne, Centre, Pays-de-Loire, Poitou-Charentes)’, for their generous and continuous support for our clinical and basic research work. Our group is supported by several grants from the (Hospital Clinical Research Program from the French national cancer institute to MM).
REFERENCES 1 Russell N, Kjeldsen L, Craddock C, Pagliuca A, Yin J, Clark R et al. A comparative assessment of the curative potential of reduced intensity allografts in acute myeloid leukaemia. Leukemia 2014; e-pub ahead of print 7 November 2014; doi:10.1038/leu.2014.319. 2 Mohty M, de Lavallade H, El-Cheikh J, Ladaique P, Faucher C, Furst S et al. Reduced intensity conditioning allogeneic stem cell transplantation for patients with acute myeloid leukemia: long term results of a 'donor' versus 'no donor' comparison. Leukemia 2009; 23: 194–196. 3 Versluis J, Labopin M, Niederwieser D, Socie G, Schlenk RF, Milpied N et al. Prediction of non-relapse mortality in recipients of reduced intensity conditioning allogeneic stem cell transplantation with AML in first complete remission. Leukemia 2014; 29: 51–57. 4 Baron F, Labopin M, Niederwieser D, Vigouroux S, Cornelissen JJ, Malm C et al. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation. Leukemia 2012; 26: 2462–2468. 5 McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400. 6 Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763. 7 Mohty M, Apperley JF.. Long-term physiological side effects after allogeneic bone marrow transplantation. Hematology Am Soc Hematol Educ Program 2010; 2010: 229–236. 8 Mengarelli A, Iori A, Guglielmi C, Romano A, Cerretti R, Torromeo C et al. Standard versus alternative myeloablative conditioning regimens in allogeneic hematopoietic stem cell transplantation for high-risk acute leukemia. Haematologica 2002; 87: 52–58. 9 Kharfan-Dabaja MA, Labopin M, Bazarbachi A, Hamladji RM, Blaise D, Socie G et al. Comparing i.v. BU dose intensity between two regimens (FB2 vs FB4) for allogeneic HCT for AML in CR1: a report from the Acute Leukemia Working Party of EBMT. Bone Marrow Transplant 2014; 49: 1170–1175. 10 Mohty M, Malard F, Blaise D, Milpied N, Furst S, Tabrizi R et al. Reduced-toxicity conditioning with fludarabine, once-daily intravenous busulfan, and antithymocyte globulins prior to allogeneic stem cell transplantation: results of a multicenter prospective phase 2 trial. Cancer 2014; 121: 562–569. 11 Mohty M, Malard F, Savani BN.. High-dose total body irradiation and myeloablative conditioning before allogeneic stem cell transplantation: time to rethink? Biol Blood Marrow Transplant 2014; 21: 620–624. 12 Malard F, Chevallier P, Guillaume T, Delaunay J, Rialland F, Harousseau JL et al. Continuous reduced nonrelapse mortality after allogeneic hematopoietic stem cell transplantation: a single-institution's three decade experience. Biol Blood Marrow Transplant 2014; 20: 1217–1223.
© 2015 Macmillan Publishers Limited
