- Email: [email protected]
Transplantations in Adult Acute Lymphoblastic Leukemia–Grounds for Optimism?
ALL
Leukemia 2008 Proceedings
Transplantations in Adult Acute Lymphoblastic Leukemia–Grounds for Optimism? Anthony H. Goldstone Abstract The large MRC/ECOG Adult Acute Lymphoblastic Leukemia Study establishes the value of sibling donor allogeneic transplantation in patients with standard risk, demonstrating superior outcome to conventional chemotherapy. The small but significant number of patients having matched unrelated donor transplantations on this study protocol appear to do well and might establish the value of such an approach for those without a sibling. Reduced-intensity conditioning might begin to address the transplantation-related mortality problems of the older patients. The youngest adults might not need to undergo transplantation at all. If they are now treated on pediatric chemotherapy protocols, their outcome appears to improve significantly. Clinical Lymphoma & Myeloma, Vol. 9, Suppl. 3, S211-S213, 2009; DOI: 10.3816/CLM.2009.s.014 Keywords: Donor vs. no donor, Philadelphia chromosome
Introduction We know that, in general, adult acute lymphoblastic leukemia (ALL) has a very poor outcome compared with outcome in children. It is clear, however, that the disease is curable but only in a minority of patients. Approximately one-third are cured. This is despite the fact that complete remission (CR) is very high, close to 90% in some studies.1 The problem is that few patients remain in remission despite the fact that, as in pediatric ALL, the treatment is initially very intensive throughout induction and consolidation, and maintenance treatment typically continues for ≥ 2 further years. The evidence is that many patients must be undertreated in that relapse rates are high, yet it appears difficult to conceive how chemotherapy could contribute any more without the introduction of new drugs. Currently, the promise of a range of effective new drugs is not very solid. This disease is unusual compared with adult acute myeloid leukemia (AML) in that a significant proportion of patients in CR die in CR. This is not just in the group receiving allogeneic transplantation but also in the group not undergoing a transplantation. The level of nonrelapse mortality in the high-risk “no donor” group in UKALL 12/ECOG 2993 is around 12%.1 This is a level considerably higher than that usually observed in AML protocols. Department of Haematology, University College London Hospitals, London, United Kingdom Submitted: May 8, 2009; Accepted: Jul 6, 2009 Address for correspondence: A.H. Goldstone, CBE FRCP, Department of Haematology, University College London Hospitals, 235 Euston Rd, London NW1 2BU, United Kingdom Fax: 44-20-7380-9153; e-mail: [email protected]
This means that the net treatment-related mortality (TRM) associated with transplantation might be considered less unattractive than initially thought; for instance, if 25% of a particular group have a TRM associated with transplantation but would have had a 12% TRM without it, then the net incremental TRM of transplantation of 25% – 12% = +13%. In adult ALL, where the CR rate is very high, we have few totally new agents available, though there is a possibility that anti-CD20 agents and other monoclonal antibodies (eg, anti-CD22) might improve the freedom from relapse in some patients already in remission. At this stage, however, until we have totally novel agents available, careful risk-benefit analysis is the only way to assign current therapies appropriately. This raises the possibility that the graft-versus-leukemia (GVL) effect, well-recognized in this disease,2 can be harnessed in more patients safely to reduce the amount of relapse without losing the patient to the problems of nonrelapse mortality frequently associated with allogeneic transplantation but unrelated-donor transplantation in particular. The value of unrelated-donor transplantations of potentially reduced toxicity will need to be assessed.3 Herein, we explore the possibility of the extension of allogeneic transplantation using as a basis for argument the biggest study of adult ALL described so far, the MRC UKALL 12/ECOG 2993 trial.
Original Rationale for the MRC UKALL 12/ECOG 2993 Study From 1993 In relation to this study, the first rationale was that we wished to study any potential GVL effect as previously described in ALL and attempt to substantiate the published data supporting allogeneic transplantation in first CR for Philadelphia chromosome–positive
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009
| S211
Transplantations in Adult ALL (Ph+) and other high-risk patients. Our hypothesis, therefore, posed the question: “Could the allogeneic GVL effect improve the outcome for all adult patients with ALL?” The second hypothesis of the study asked whether a single autologous transplantation could be at least as effective as standard consolidation/maintenance therapy for patients lacking a family donor. The structure was thus to include patients between 15 years and 50 years (later, 55 years) and assess which of these had an HLA-compatible family donor. If they had a donor, they would be assigned to receive a sibling allograft in first remission. If they did not have a donor, they would be randomized in remission between an autologous transplantation in first remission versus consolidation maintenance chemotherapy. Only patients who were Ph+ were allowed to be subjected to matched unrelated donor (MUD) transplantation while in first remission, a sibling donor, or, where relevant, an autologous transplantation if they had no donor. We considered patients as high-risk patients if they had any of the following characteristics: -
Age > 35 years White blood cell count (WBC) > 30,000/μL (B-lineage) WBC > 100,000/μL (T-lineage) Time to CR > 4 weeks Cytogenetics, t(4;11)t(8;14), complex karyotype, low hypodiploidy, triploidy
It is now generally agreed that the only acceptable way to compare a group of patients undergoing transplantation with others of comparable status, but not undergoing transplantation, is on a “donor-versus-no-donor basis.” Among our group of patients with donors, there was a reduced relapse rate, but the high transplantation-related mortality of highrisk patients (36% at 2 years) abrogated the reduction in relapse such that a definite advantage could not be demonstrated for allogeneic transplantations among high-risk patients, although the 5-year survival for the patients with a donor was 41% compared with the 35% overall survival for those without a donor (P = .2). The overall benefit for a donor in standard-risk patients appears at all ages, but in the younger patients, there is the possibility that more aggressive pediatric-type regimens currently being offered to adolescents and young adults might afford a better long-term outcome than the conventional chemotherapy such as the UKALL 12/ECOG 2993 regimen in these age groups, thus reducing the need for allogeneic transplantation.4 If the younger adults can have their outlook improved by pediatric-type protocols, the major problem would then relate to patients > 35 years-40 years with this disease. The dilemma here is clear because the outcome data with chemotherapy alone begin to deteriorate above 40 years, while the GVL effect remains a potent therapeutic modality. For the transplantation patient, the problem is also one of TRM at increasing age, except perhaps with reduced-intensity conditioning (RIC), and it is unclear whether the outcomes from chemotherapy alone and transplantation deteriorate to a comparable degree. Overall survival on a donor-versus-no-donor basis for UKALL 12/ECOG 2993 confirms the superiority of having a donor for a standard-risk patient but cannot confirm this for the high-risk Ph– patient. The implication of this is that the outcome of the very
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September 2009
group that is at the highest risk might be less likely to improve after allogeneic transplantation. It is likely that the most important risk factor, for the toxicity of transplantation, is age. This raises the possibility that reduced-intensity transplantation, which relies almost entirely on harnessing the GVL effect as opposed to the dose-escalation effect, might be relevant to ALL, particularly in the older patient. This already seems to be coming established in AML. In most circumstances, in ALL and AML, increasing use of RIC has emerged without relevant prospective data and mostly from registry evidence. The “registry problem” is a classic one with mixed conditioning regimens and groups of patients with different statuses of disease grouped together.5,6 What we have been fortunate to see, and have the possibility to analyze, is a group of patients from the large MRC/ECOG study who were subjected to unrelated-donor allogeneic transplantation in first remission. When this study was designed > 15 years ago, a matched unrelated donor was only an option for patients at extremely high risk, such as those with a Ph chromosome. A group of other patients who were Ph negative was, however, grafted off-study in first remission with an unrelated donor. Because these patients were off-study, the data from them need to be interpreted with caution, but clearly, it is highly likely that the selection of such patients for transplantation was based on the perception of their clinicians that they represented “high risk.” There is other data, from registries and single centers, that indicate that an MUD transplantation is an appropriate option for patients with ALL at high risk who are in first CR.3 If one looks at the groups of patients having MUD transplantations, overall, the numbers are small, but the relapse-free survival from transplantation is significantly superior in the Ph– group versus Ph+, and the OS for the Ph– group is 58% (n = 32; unpublished data). Relapse is low (3 of 32 patients in the Ph– group). It might make little difference whether the stem cells are blood or marrow derived. The outcomes of all first-CR MUD transplantations in UKALL 12/ECOG 2993 are clearly affected by the age of the patient: 58% OS in those < 35 years of age and 28% OS in those > 35 years. This must affect thinking regarding the selection of MUD transplantation for the patients aged > 35 years to 40 years and for sibling transplantation, for which the age factor will bear heavily. At present, a group of adults with ALL in whom the risk of relapse is less than the risk of allogeneic bone marrow transplantation cannot be defined. One might suppose that one of the major questions that now remains is whether an unrelated-donor transplantation is also appropriate for patients at standard risk; currently, there is at least 1 study that prospectively compares the outcome of matched related and matched unrelated-donor transplantations for patients with ALL, and the outcome between the 2 appears virtually identical.3
Conclusion Several trials and metaanalyses confirm that there is a GVL effect in adult ALL that produces a significant reduction in relapse. Unfortunately, the net beneficial outcome effect of this reduction in relapse is significantly reduced in the patients at higher risk by considerable TRM. Of the risk factors that contribute to the greatest degree, the most important is probably age. This means that for the patient aged > 40 years, and the median age of incidence of adults
Anthony H. Goldstone for ALL is around 60 years, the allogeneic transplantation must be undertaken with considerable caution. However, in general terms, the allogeneic transplantation offers an extremely attractive option of shortening what is otherwise the most complex and long treatment in the whole of adult clinical oncology. If it could be extended to a constituency beyond those who simply have a matched sibling available, then it would become a very relevant and important clinical treatment. Unrelated-donor transplantations, largely off-study and from Registry data but with a few prospective studies, appear, superficially, to offer an attractive way forward for patients without a sibling or matched family donor. For the younger adult, the more intensive pediatric protocols are currently being examined through adolescent patients and up to groups of patients in their mid-twenties and older. These protocols appear to be giving attractive and acceptable results, with survival data beyond that of conventional adult protocols for this disease. They might represent a way forward for the young adult without having to undertake the risk of allogeneic transplantation. For the older adult (> 40 years), the risk from an unrelated-donor allograft might be unacceptable, except possibly by using RIC. In conclusion, it might be that the patients at high risk, aged 25 years to 45 years, with adult ALL in first CR and without a potential sibling donor, might be the first group to benefit from an unrelated-donor allograft. The patients younger than that might be getting acceptable results on the pediatric protocols, and the
patients older than that might be entertaining a risk too high to proceed with that form of treatment at the present time.
Disclosures Dr. Goldstone has received grant or research support, served as a paid consultant, and served on an advisory committee or review panel for Roche Pharmaceuticals.
References 1. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard risk acute lymphoblastic leukaemia, the greatest benefit is achieved from a matched sibling allogeneic transplantion in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG 2993). Blood 2008; 111:1827-33. 2. Weiden PL, Doney K, Storb R, et al. Antihuman thymocyte globulin for prophylaxis of graft-versus-host disease. A randomised trial in patients with leukaemia treated with HLA-identifal sibling marrow grafts. Transplantation 1979; 27:227-30. 3. Kiehl MG, Kraut L, Schwerdtfeger R, et al. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukaemia: no difference in related compared with unrelated transplant in first complete remission. J Clin Oncol 2004; 22:2816-25. 4. Ramanujachar R, Richards S, Hann I, et al. Adolescents with acute lymphoblastic leukaemia: emerging rom the shadow of paediatric and adult treatment protocols. Pediatr Blood Cancer 2006; 47:748-56. 5. Mohty M, Labopin M, Tabrizzi R, et al. Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukaemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Haematologica 2008; 93:303-6. 6. Martino R, Giralt S, Caballero MD, et al. Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning in acute lymphoblastic leukaemia: a feasibility study. Haematologica 2003; 88:555-60.
Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009
| S213
Leukemia 2008 Proceedings
Transplantations in Adult Acute Lymphoblastic Leukemia–Grounds for Optimism? Anthony H. Goldstone Abstract The large MRC/ECOG Adult Acute Lymphoblastic Leukemia Study establishes the value of sibling donor allogeneic transplantation in patients with standard risk, demonstrating superior outcome to conventional chemotherapy. The small but significant number of patients having matched unrelated donor transplantations on this study protocol appear to do well and might establish the value of such an approach for those without a sibling. Reduced-intensity conditioning might begin to address the transplantation-related mortality problems of the older patients. The youngest adults might not need to undergo transplantation at all. If they are now treated on pediatric chemotherapy protocols, their outcome appears to improve significantly. Clinical Lymphoma & Myeloma, Vol. 9, Suppl. 3, S211-S213, 2009; DOI: 10.3816/CLM.2009.s.014 Keywords: Donor vs. no donor, Philadelphia chromosome
Introduction We know that, in general, adult acute lymphoblastic leukemia (ALL) has a very poor outcome compared with outcome in children. It is clear, however, that the disease is curable but only in a minority of patients. Approximately one-third are cured. This is despite the fact that complete remission (CR) is very high, close to 90% in some studies.1 The problem is that few patients remain in remission despite the fact that, as in pediatric ALL, the treatment is initially very intensive throughout induction and consolidation, and maintenance treatment typically continues for ≥ 2 further years. The evidence is that many patients must be undertreated in that relapse rates are high, yet it appears difficult to conceive how chemotherapy could contribute any more without the introduction of new drugs. Currently, the promise of a range of effective new drugs is not very solid. This disease is unusual compared with adult acute myeloid leukemia (AML) in that a significant proportion of patients in CR die in CR. This is not just in the group receiving allogeneic transplantation but also in the group not undergoing a transplantation. The level of nonrelapse mortality in the high-risk “no donor” group in UKALL 12/ECOG 2993 is around 12%.1 This is a level considerably higher than that usually observed in AML protocols. Department of Haematology, University College London Hospitals, London, United Kingdom Submitted: May 8, 2009; Accepted: Jul 6, 2009 Address for correspondence: A.H. Goldstone, CBE FRCP, Department of Haematology, University College London Hospitals, 235 Euston Rd, London NW1 2BU, United Kingdom Fax: 44-20-7380-9153; e-mail: [email protected]
This means that the net treatment-related mortality (TRM) associated with transplantation might be considered less unattractive than initially thought; for instance, if 25% of a particular group have a TRM associated with transplantation but would have had a 12% TRM without it, then the net incremental TRM of transplantation of 25% – 12% = +13%. In adult ALL, where the CR rate is very high, we have few totally new agents available, though there is a possibility that anti-CD20 agents and other monoclonal antibodies (eg, anti-CD22) might improve the freedom from relapse in some patients already in remission. At this stage, however, until we have totally novel agents available, careful risk-benefit analysis is the only way to assign current therapies appropriately. This raises the possibility that the graft-versus-leukemia (GVL) effect, well-recognized in this disease,2 can be harnessed in more patients safely to reduce the amount of relapse without losing the patient to the problems of nonrelapse mortality frequently associated with allogeneic transplantation but unrelated-donor transplantation in particular. The value of unrelated-donor transplantations of potentially reduced toxicity will need to be assessed.3 Herein, we explore the possibility of the extension of allogeneic transplantation using as a basis for argument the biggest study of adult ALL described so far, the MRC UKALL 12/ECOG 2993 trial.
Original Rationale for the MRC UKALL 12/ECOG 2993 Study From 1993 In relation to this study, the first rationale was that we wished to study any potential GVL effect as previously described in ALL and attempt to substantiate the published data supporting allogeneic transplantation in first CR for Philadelphia chromosome–positive
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009
| S211
Transplantations in Adult ALL (Ph+) and other high-risk patients. Our hypothesis, therefore, posed the question: “Could the allogeneic GVL effect improve the outcome for all adult patients with ALL?” The second hypothesis of the study asked whether a single autologous transplantation could be at least as effective as standard consolidation/maintenance therapy for patients lacking a family donor. The structure was thus to include patients between 15 years and 50 years (later, 55 years) and assess which of these had an HLA-compatible family donor. If they had a donor, they would be assigned to receive a sibling allograft in first remission. If they did not have a donor, they would be randomized in remission between an autologous transplantation in first remission versus consolidation maintenance chemotherapy. Only patients who were Ph+ were allowed to be subjected to matched unrelated donor (MUD) transplantation while in first remission, a sibling donor, or, where relevant, an autologous transplantation if they had no donor. We considered patients as high-risk patients if they had any of the following characteristics: -
Age > 35 years White blood cell count (WBC) > 30,000/μL (B-lineage) WBC > 100,000/μL (T-lineage) Time to CR > 4 weeks Cytogenetics, t(4;11)t(8;14), complex karyotype, low hypodiploidy, triploidy
It is now generally agreed that the only acceptable way to compare a group of patients undergoing transplantation with others of comparable status, but not undergoing transplantation, is on a “donor-versus-no-donor basis.” Among our group of patients with donors, there was a reduced relapse rate, but the high transplantation-related mortality of highrisk patients (36% at 2 years) abrogated the reduction in relapse such that a definite advantage could not be demonstrated for allogeneic transplantations among high-risk patients, although the 5-year survival for the patients with a donor was 41% compared with the 35% overall survival for those without a donor (P = .2). The overall benefit for a donor in standard-risk patients appears at all ages, but in the younger patients, there is the possibility that more aggressive pediatric-type regimens currently being offered to adolescents and young adults might afford a better long-term outcome than the conventional chemotherapy such as the UKALL 12/ECOG 2993 regimen in these age groups, thus reducing the need for allogeneic transplantation.4 If the younger adults can have their outlook improved by pediatric-type protocols, the major problem would then relate to patients > 35 years-40 years with this disease. The dilemma here is clear because the outcome data with chemotherapy alone begin to deteriorate above 40 years, while the GVL effect remains a potent therapeutic modality. For the transplantation patient, the problem is also one of TRM at increasing age, except perhaps with reduced-intensity conditioning (RIC), and it is unclear whether the outcomes from chemotherapy alone and transplantation deteriorate to a comparable degree. Overall survival on a donor-versus-no-donor basis for UKALL 12/ECOG 2993 confirms the superiority of having a donor for a standard-risk patient but cannot confirm this for the high-risk Ph– patient. The implication of this is that the outcome of the very
S212
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September 2009
group that is at the highest risk might be less likely to improve after allogeneic transplantation. It is likely that the most important risk factor, for the toxicity of transplantation, is age. This raises the possibility that reduced-intensity transplantation, which relies almost entirely on harnessing the GVL effect as opposed to the dose-escalation effect, might be relevant to ALL, particularly in the older patient. This already seems to be coming established in AML. In most circumstances, in ALL and AML, increasing use of RIC has emerged without relevant prospective data and mostly from registry evidence. The “registry problem” is a classic one with mixed conditioning regimens and groups of patients with different statuses of disease grouped together.5,6 What we have been fortunate to see, and have the possibility to analyze, is a group of patients from the large MRC/ECOG study who were subjected to unrelated-donor allogeneic transplantation in first remission. When this study was designed > 15 years ago, a matched unrelated donor was only an option for patients at extremely high risk, such as those with a Ph chromosome. A group of other patients who were Ph negative was, however, grafted off-study in first remission with an unrelated donor. Because these patients were off-study, the data from them need to be interpreted with caution, but clearly, it is highly likely that the selection of such patients for transplantation was based on the perception of their clinicians that they represented “high risk.” There is other data, from registries and single centers, that indicate that an MUD transplantation is an appropriate option for patients with ALL at high risk who are in first CR.3 If one looks at the groups of patients having MUD transplantations, overall, the numbers are small, but the relapse-free survival from transplantation is significantly superior in the Ph– group versus Ph+, and the OS for the Ph– group is 58% (n = 32; unpublished data). Relapse is low (3 of 32 patients in the Ph– group). It might make little difference whether the stem cells are blood or marrow derived. The outcomes of all first-CR MUD transplantations in UKALL 12/ECOG 2993 are clearly affected by the age of the patient: 58% OS in those < 35 years of age and 28% OS in those > 35 years. This must affect thinking regarding the selection of MUD transplantation for the patients aged > 35 years to 40 years and for sibling transplantation, for which the age factor will bear heavily. At present, a group of adults with ALL in whom the risk of relapse is less than the risk of allogeneic bone marrow transplantation cannot be defined. One might suppose that one of the major questions that now remains is whether an unrelated-donor transplantation is also appropriate for patients at standard risk; currently, there is at least 1 study that prospectively compares the outcome of matched related and matched unrelated-donor transplantations for patients with ALL, and the outcome between the 2 appears virtually identical.3
Conclusion Several trials and metaanalyses confirm that there is a GVL effect in adult ALL that produces a significant reduction in relapse. Unfortunately, the net beneficial outcome effect of this reduction in relapse is significantly reduced in the patients at higher risk by considerable TRM. Of the risk factors that contribute to the greatest degree, the most important is probably age. This means that for the patient aged > 40 years, and the median age of incidence of adults
Anthony H. Goldstone for ALL is around 60 years, the allogeneic transplantation must be undertaken with considerable caution. However, in general terms, the allogeneic transplantation offers an extremely attractive option of shortening what is otherwise the most complex and long treatment in the whole of adult clinical oncology. If it could be extended to a constituency beyond those who simply have a matched sibling available, then it would become a very relevant and important clinical treatment. Unrelated-donor transplantations, largely off-study and from Registry data but with a few prospective studies, appear, superficially, to offer an attractive way forward for patients without a sibling or matched family donor. For the younger adult, the more intensive pediatric protocols are currently being examined through adolescent patients and up to groups of patients in their mid-twenties and older. These protocols appear to be giving attractive and acceptable results, with survival data beyond that of conventional adult protocols for this disease. They might represent a way forward for the young adult without having to undertake the risk of allogeneic transplantation. For the older adult (> 40 years), the risk from an unrelated-donor allograft might be unacceptable, except possibly by using RIC. In conclusion, it might be that the patients at high risk, aged 25 years to 45 years, with adult ALL in first CR and without a potential sibling donor, might be the first group to benefit from an unrelated-donor allograft. The patients younger than that might be getting acceptable results on the pediatric protocols, and the
patients older than that might be entertaining a risk too high to proceed with that form of treatment at the present time.
Disclosures Dr. Goldstone has received grant or research support, served as a paid consultant, and served on an advisory committee or review panel for Roche Pharmaceuticals.
References 1. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard risk acute lymphoblastic leukaemia, the greatest benefit is achieved from a matched sibling allogeneic transplantion in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG 2993). Blood 2008; 111:1827-33. 2. Weiden PL, Doney K, Storb R, et al. Antihuman thymocyte globulin for prophylaxis of graft-versus-host disease. A randomised trial in patients with leukaemia treated with HLA-identifal sibling marrow grafts. Transplantation 1979; 27:227-30. 3. Kiehl MG, Kraut L, Schwerdtfeger R, et al. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukaemia: no difference in related compared with unrelated transplant in first complete remission. J Clin Oncol 2004; 22:2816-25. 4. Ramanujachar R, Richards S, Hann I, et al. Adolescents with acute lymphoblastic leukaemia: emerging rom the shadow of paediatric and adult treatment protocols. Pediatr Blood Cancer 2006; 47:748-56. 5. Mohty M, Labopin M, Tabrizzi R, et al. Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukaemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Haematologica 2008; 93:303-6. 6. Martino R, Giralt S, Caballero MD, et al. Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning in acute lymphoblastic leukaemia: a feasibility study. Haematologica 2003; 88:555-60.
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