EBMT2008_1_21:EBMT :22 Pagina 356 CHAPTER 20. HSCT for acute myeloid leukaemia in adults. R. Varaldo, F. Frassoni

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1 EBMT2008_1_21:EBMT :22 Pagina 356 * CHAPTER 20 HSCT for acute myeloid leukaemia in adults R. Varaldo, F. Frassoni

2 EBMT2008_1_21:EBMT :22 Pagina 357 CHAPTER 20 AML in adults 1. Introduction Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells which lose the ability to differentiate normally and to respond to normal regulators of proliferation. AML is the most common adult leukaemia, with an annual incidence of approximately 2.4 cases per 100,000 population up to the sixth decade, rising to cases in the seventh decade (1). The median age at presentation is approximately 68 years but the majority of data on AML treatment refer to younger patient (<60 years). Thus, 50% or more patients are generally neglected by the majority of clinical trials and reports in the journals and at meetings. AML is initially with chemotherapy (CT) to induce remission. The treatment plan involves a remission induction phase aimed to establishing a complete remission (CR) and a post-induction phase aimed to eradicating/reducing residual disease. Combination CT induces CR in an average of 60 to 80% of adults aged less than 60 years. Once CR has been achieved, further intensive therapy is needed to prevent relapse. Post-remission therapy for patients under the age 60 includes CT or HSCT. HSCT is one type of post-remission therapy. In general, HSCT are performed after 2 or 3 courses of chemotherapy. When HSCT is performed in remission, the leukaemic mass has been reduced by least of two logs with respect to the onset of the disease. Who should be transplanted for AML? In 2007 this is still an open question. To find the answer to this question, one of the most important areas of interest in the treatment of AML over the past decade has been the clarification of prognostic factors, leading to much-improved risk determination. All major cooperative groups that have studied the treatment of AML have identified cytogenetic abnormalities at presentation and time to achieve remission as the major disease-specific prognostic factors (2). Currently AML patients are stratified into 3 main risk categories based on cytogenetics, molecular biology and response to initial CT. The difficulty with using cytogenetic grouping as a risk factor is that most patients fall in the intermediate risk group, and the majority of these have a normal karyotype. Between 40 and 50% of young adult AML patients in Europe and the USA have been found to have a normal karyotype. The intermediate group, unlike the favourable or the unfavourable cytogenetics group, comprises a very heterogeneous mix of patients, with some having a poor prognosis and others having a better prognosis. However, molecular genetics is continuously defining new biological entities. This, in turn, identifies new prognostic factors and often moves the new AML subset into another prognostic group, particularly within the intermediate and favourable groups. Unfavourable prognosis is associated with several of these entities, including: - the Wilms tumour gene, WT1 HAEMATOPOIETIC STEM CELL TRANSPLANTATION 357

3 EBMT2008_1_21:EBMT :22 Pagina the genes for the apoptosis regulators B-cell lymphoma protein 2 (BCL-2): BCL2, and BCL-2 associated X protein, BAX - the brain and acute leukaemia cytoplasmic gene, BAALC - the ecotropic viral integration site 1 gene, EVI1 - the FMS-like tyrosine kinase type 3 gene, FLT3 - KIT, ERG, and the mixed-lineage leukaemia gene, MLL. Some mutations of specific genes confer a more favourable prognosis; most notably, mutations in the genes for CCAAT enhancer binding protein-a (C/EBP-a), CEBPA, and nucleophosmin, NPM1 (3 5). 2. Autologous haematopoietic stem cell transplantation The available data indicate that better outcome (less relapse) is achieved when cells are harvested after the second or third course of chemotherapy. In principle, autologous HSCT has several potential advantages over allogeneic HSCT: - a matched donor is not needed - there is no risk of complications such as graft-versus-host disease (GvHD) - the convalescence period is much shorter and simpler - the immunological reconstitution is much faster and more complete - the work of nurses and physicians is much easier. However, there are three major important disadvantages: - the relapse rate is much higher, probably due to lack of graft-versus-leukaemia (GvL) effect and the contamination of the graft with leukaemic cells - there are often difficulties in collecting sufficient HSC - in high-risk leukaemia the role of autologous HSCT is minimal since the final outcome is dismal. In general, the results of autograft for AML have remained constant over the last 10 years. There has been a reduction of transplant related mortality (TRM) probably due to better supportive therapy. The leukaemia free survival (LFS) ranges from 40 to 50% at 3 years. The data of the Acute Leukaemia Working Party (ALWP) registry from 1996 to 2001, encompassing 2100 patients autografted for AML in 1CR indicate the following outcomes at 5 years: LFS = 43%, OS = 51%, RR = 53%, TRM = 9% (unpublished data from ALWP-EBMT). This is an important achievement, especially considering that autologous HSCT can be now offered to patients up to 65 years and beyond. Auto-HSCT produces durable second remission in 25 30% of patients with relapsed AML who achieved a second CR, but its low TRM is offset by a high relapse rate (6). For a number of reasons auto-hsct has become less appealing in recent years. From the scientific point of view the reason lies in the fact that there has not been any 358 THE EBMT HANDBOOK 2008 REVISED EDITION

4 EBMT2008_1_21:EBMT :22 Pagina 359 CHAPTER 20 AML in adults improvement in methods of reducing relapse. There are centres which continue to perform auto-hsct using purged graft. Their results are generally superior to those reported with the unpurged marrow. However, since there has never been a randomised study, the majority of AML experts remain sceptical about this manoeuvre. In the autografting setting, it is still unclear whether a better outcome can be obtained with PB compared with BM. How many patients reach the possibility of undergoing auto-hsct? One of the major drawbacks of autografting studies in AML has been the scarce accrual of patients. In general no more than 50 to 60% of patients who in principle were allocated to auto-hsct actually reach the transplant. This has mainly been caused by early relapse of leukaemia, or the harvest of an insufficient haematopoietic cell graft. Currently, autografting is restricted to older patients, patients with APL in second molecular remission and younger patients lacking a sibling or matched unrelated donor. 3. Allogeneic haematopoietic stem cell transplantation Allo-HSCT has had a tremendous relevance in AML. In the last 20 years, thousands of AML patients have been cured by allo-hsct. These patients would have otherwise died of their disease. In the last five years a variety of data have emerged which clearly indicate that: - the results of MUD have improved and are still improving - the results of cord blood transplant are equivalent to the results of MUD transplants and seem to have much more scope for improvement in the near future - the age limit remains but older patients are increasingly considered for a transplant and several strategies have been designed for reducing transplant-related toxicity. A transplant consists of several procedures. Several tasks need to be accomplished for a successful transplant: - reducing the tumour burden (it is believed that the conditioning regimen reduces the tumour burden by 3-4 logs) - immunosuppression; without this the risk that the graft is rejected is very high - the prevention of GvHD - the prevention and treatment of the infections (bacterial and fungal) linked to neutropenia in the first phase of transplant and the later viral and fungal infections related to the slow recovery of T-cells and immune function in general. The wide variation in the preparative regimens used is one of the major causes of the differences in outcome in different studies. Besides the considerable variation in the regimens utilised to prepare the patient for HSCT, there are also different sources of haematopoietic cells that can be used. The goal of performing a HAEMATOPOIETIC STEM CELL TRANSPLANTATION 359

5 EBMT2008_1_21:EBMT :22 Pagina 360 transplant which maintains the positive effect of allo-reactivity while removing the detrimental effect is being approached but a true intelligent manipulation has yet to come. The HLA barrier remains the most important factor. The best results are those using an HLA compatible family donor. Most patients do not have a compatible HLA family donor. Thus, the use of partially matched family donors and matched unrelated donors is increasing HLA compatible sibling transplant This type of HSCT is considered the standard reference for any other transplant. There has been a considerable improvement of the results starting from 1990 compared with the antecedent period, and there is evidence of ongoing improvement. The current results for AML patients transplanted in CR1 give a probability of DFS ranging from 45 to 70% and the EBMT registry data of the last 5 7 years indicate approximately 55 60% DFS. With respect to the past, centres are now transplanting older patients. There is a variation among centres depending on the type of patients transplanted and on the experience and skill of the Centre (7). The relapse rate continues to be approximately 20 25% for patients with intermediate risk. The current results from the ALWP-EBMT registry are shown in Figure 1. Figure 1: Myeloablative HSCT in AML - HLA compatible sibling donor ALWP-EBMT 1.0 Leukaemia Free Survival CR1 patients (n=2808) 55 ± 1% 0.4 CR2 patients (n=451) 44 ± 3% Generated by the ALWP (Myriam Labopin and Vanderson Rocha) 360 THE EBMT HANDBOOK 2008 REVISED EDITION

6 EBMT2008_1_21:EBMT :22 Pagina 361 CHAPTER 20 AML in adults 3.2. Matched unrelated donor transplants This type of HSCT, utilising the worldwide donor registry network, represents the major effort of transplant centres in the last decade. There has been a significant effort to create a network from which matched unrelated donors can be available and the network encompasses now more than 10 million potential donors. Several studies have shown that the results of matched unrelated donor (MUD) transplants can approach those of transplant using a HLA compatible sibling donor. The continuous improvement in HLA typing is associated with improved results. However, while the outcome is improving, this type of transplant is still associated with considerable morbidity and mortality. New and interesting aspects of HLA matching are also emerging (8, 9) which may be useful in guiding donor selection. At the same time the high resolution HLA typing restricts the number of suitable donors. In addition, although the time from the beginning of search has shortened, a number of patients with AML often need a transplant in a very short period of time. These are some of the reasons why alternative source such as Cord Blood Unit is emerging as an alternative strategy. The current results from the ALWP-EBMT registry since the year 2000 are shown in Figure 2. Figure 2: Myeloablative HSCT in AML - matched unrelated donors ALWP-EBMT 1.0 Leukaemia Free Survival CR1 patients (n=708) 46 ± 3% CR2 patients (n=424) 37 ± 4% Generated by the ALWP (Myriam Labopin and Vanderson Rocha) HAEMATOPOIETIC STEM CELL TRANSPLANTATION 361

7 EBMT2008_1_21:EBMT :22 Pagina Source of haematopoietic stem cells In the past decade, the use of peripheral blood (PB) as a source of haematopoietic stem cells for allogeneic transplantation has increased considerably. A large number of retrospective studies and also several prospective randomised trials have compared the outcome of patients receiving allografts with bone marrow (BM) versus PB, using an identical sibling; in all studies PB has resulted in faster engraftment and shorter hospital stay. In most studies the incidence and severity of acute GvHD (agvhd) (10, 11) has been similar with PB and BM; PB on the other hand has been associated with more chronic GvHD (cgvhd). In the same period, other studies on BM and PB transplantation have drawn attention to the importance of the dose of stem cells infused; a lower transplantrelated mortality (TRM) and, in some studies, a lower relapse rate after transplantation have been observed in patients undergoing allografting who receive a higher stem cell dose (12); however, this holds only for BM transplant recipients. Finally, the available data suggests that with standard conditioning the outcome for patients with low-risk disease might be better with BM; for patients with high-risk disease it might be better with PB grafts. 3.4 Umbilical cord blood transplants (CBT) Two relatively recent publications have shown that CBT are not inferior to matched unrelated transplants in acute leukaemias (13, 14). In addition, if CBT could overcome the problem of delayed/failure to engraft it is likely that it could become the best choice for unrelated transplants (9, 13 15). In fact compared with MUD several advantages exist: - less restrictive HLA compatibility requirements - time to transplant is far more rapid - absence of any risk for the donor. Currently, several means to improve engraftment are being evaluated. They include: cell expansion, double cord transplant, co-infusion of haploidentical donor CD34 selected cells, co-infusion of MSC, and direct intra-bone transplant. In addition, there are several reports indicating that high resolution matching might improve the outcome of UCB transplants (9); this would mean there would be a need to expand the number of banked units Haplo-identical transplants Haplo-identical transplant has been developed by the Perugia group. The approach is based on the concept of complete T-cell depletion and the use of megadoses of stem cells (16, 17). No GvHD prophylaxis is given. The most recent publication reports 362 THE EBMT HANDBOOK 2008 REVISED EDITION

8 EBMT2008_1_21:EBMT :22 Pagina 363 CHAPTER 20 AML in adults an event-free survival rate was 48 ± 8% and 46 ± 10%, respectively, for the 42 AML and 24 ALL patients receiving transplantation in remission. Most patients with advanced disease simply do not make it to transplantation. In other words, those patients who do receive MUD transplants for advanced AML are a select group who survived long enough to undergo transplantation. In comparison, haploidentical transplant recipients represent a group of patients who are transplanted much sooner; many of them would never have survived long enough to undergo an MUD transplantation. Finally, a relevant impact of NK allo-reactivity in controlling AML is increasingly being shown (16, 18). From these studies the possibility of utilising NK allo-reactivity outside the transplant setting has been derived Reduced-intensity conditioning Reduced-intensity conditioning has become an accepted treatment modality. Despite its wide use, to date there have been no prospective comparative studies. Available information is based on data from phase II clinical studies (19) and some retrospective comparative data. The best data in patients with AML have come from a multi-centre study in the USA and Europe, referred to as the Consortium Study (20). One hundred and twenty-two AML patients, with approximately equal numbers of related and unrelated donor-recipient pairs, were included in this study. The most important reason for reduced-intensity conditioning was age or significant comorbidity. Engraftment was prompt in all patients. The overall survival rate at 2 years was 48%, and patients receiving transplantation during CR1 had 2-year overall survival rates of 44% (related HSCT) and 63% (unrelated HSCT). Cumulative incidences of acute GvHD (grades 2 4) were 35% at 180 days after related HSCT and 42% after unrelated HSCT. The probability of one of the most important complications, chronic GvHD, was 36% at 2 years (20). The preponderance of data has established reduced-intensity conditioning as a feasible option, but how feasible and how important this is in the management of AML, and how much of a difference it will make, still needs to be established in prospective studies. The only solid fact which argues in favour of reduced-intensity conditioning transplants (RIC) may be that with RIC one can offer a transplant to patients who otherwise would not have any other valid therapeutic options. The current results of RIC from the ALWP-EBMT registry are shown in Figures 3 and 4. EBMT is currently investigating in a prospective randomised trial the role of RIC HSCT in elderly patients with AML. HAEMATOPOIETIC STEM CELL TRANSPLANTATION 363

9 EBMT2008_1_21:EBMT :22 Pagina 364 Figure 3: RIC HSCT in AML - HLA compatible sibling donor ALWP-EBMT 1.0 Leukaemia Free Survival CR1 patients (n=953) 41 ± 1% CR2 patients (n=210) 37 ± 5% Generated by the ALWP (Myriam Labopin and Vanderson Rocha) Figure 4: RIC HSCT in AML - matched unrelated donors ALWP-EBMT 1.0 Leukaemia Free Survival CR1 patients (n=228) 41 ± 5% CR2 patients (n=157) 42 ± 5% Generated by the ALWP (Myriam Labopin and Vanderson Rocha) 364 THE EBMT HANDBOOK 2008 REVISED EDITION

10 EBMT2008_1_21:EBMT :22 Pagina 365 CHAPTER 20 AML in adults 3.7. Comparison of results of different strategies and the place of allogeneic HSCT in the management of AML There have been four large studies that have attempted to address which modality is better allogeneic HSCT, autologous HSCT, or chemotherapy alone. These studies have all identified patients at diagnosis and then assigned patients in first remission to allogeneic transplantation if they have a matched sibling donor, randomising the remaining patients to consolidation chemotherapy or autologous transplantation (21 23). In recent years, a popular method for assessing the role of allo-hsct in acute leukaemia has been the evaluation of whether having a family HLA matched donor was associated with an improvement in survival: the so call donor versus no-donor analysis. This method has produced conflicts in the interpretation of the results. The most recent large and important study analysing the advantage of having a family donor refers, however, to acute lymphoblastic leukaemia. A donor versus no donor analysis showed that the survival difference was significant in standard-risk patients, but not in high-risk patients (24). Recently data from some reported studies were subjected to a meta-analysis (25). The analysis was designed to include studies that had evaluated the outcome of patients with AML in CR1 by availability of a related donor using an intention to treat approach. Four of the studies had demonstrated a benefit with respect to DFS in favour of patients with a donor but as single studies this was not translated in a benefit in OS; however, an advantage in OS was demonstrated for the whole cohort of patients with donors included in the meta-analysis. When analysed by cytogenetic risk group, a significant advantage was observed for poor-risk patients with donors. For the favourable and intermediate risk group patients a survival benefit was not observed. Most experts today consider that the effect of allogeneic stem cell transplantation needs to be re-assessed in specific biological subgroups taking account, as well as classic cytogenetic stratification risk, a variety of new molecular biological data (mainly based on minimal residual disease assays) with the aim of defining a tailored therapy as has already been demonstrated in the in paediatric acute leukaemia setting. In any case, for patients with high-risk features and beyond CR1, allo-hsct remains the sole possibility of surviving. 4. Current strategy for patients with AML Taking account the above limitations, at present most experts in the field of AML treatment would suggest the following strategy: HAEMATOPOIETIC STEM CELL TRANSPLANTATION 365

11 EBMT2008_1_21:EBMT :22 Pagina For good-risk patients in first CR chemotherapy seems not inferior to transplant strategies. However, one must be sure that the schedule and protocols have been proven to provide a DFS above 60%. This because the results of HSCT now approach that outcome - Acute promyelocytic leukaemia (APL) is never recommended for a transplant if the PCR is negative because the results of CT alone are excellent. If APL patients are not in molecular remission or are in overt relapse auto or allo-bmt are an option - For intermediate risk patients, who represent the majority of patients with AML, allo-hsct probably remains the best option if a HLA matched sibling donor is available. If a HLA compatible sibling is unavailable, autograft may be a possible option; however, this choice is increasingly challenged by the results of MUD and especially of CBT - For poor-risk patients in CR1 and for all other patients who relapse during and following the planned therapy the chance of surviving without a transplant is very low. For those patients an early transplant strategy should be organised. In this area, the use of an alternative donor (see MUD or cord blood or haplo-identical transplant) represents the sole possibility of survival. In this respect, the early identification of high-risk patients is very important since the timing of a search for an alternative source of haematopoietic stem cell may be crucial for the life of the patient. 5. Conclusion There has been a paradigm shift in the field of AML treatment. Disease risk can be assessed much better than ever before and a classification into low, intermediate and high-risk should become possible for all patients. In parallel, the risks of the transplant can also be better assessed, based on patient and donor characteristics as outlined in above. In order to implement future strategies, every patient with newly diagnosed AML should have a complete assessment of disease risk and a search for a donor at diagnosis. Depending on disease risk and transplant risk, algorithms for treatment after induction and consolidation might appear as follows and be separated into planned HSCT in CR1 or delayed HSCT (see Table 1) (26). 366 THE EBMT HANDBOOK 2008 REVISED EDITION

12 EBMT2008_1_21:EBMT :22 Pagina 367 CHAPTER 20 AML in adults Table 1: Transplant algorithm for AML Disease risk Transplants in 1 st CR Low risk Intermediate risk High risk Transplants for refractory diseases Transplants in 2 nd CR Low risk High risk No transplant Transplant risk according to extended EBMT risk score (see indications) risk score 0-1 risk score 0-2 risk score 0-5 risk score 0-6 risk score 0-3 risk score 0-6 risk score >6 References 1. Ries L, Eisner M, Kosary C, et al. SEER Cancer Statistics Review, , National Cancer Institute. Bethesda, MD: National Cancer Institute Wheatley K, Burnett AK, Goldstone AH, et al. A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. Brit J Haematol 1999; 107: Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: Analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001; 98: Preudhomme C, Sagot C, Boissel N. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: A study from the Acute Leukemia French Association (ALFA). Blood 2002; 100: Falini B, Nicoletti I, Martelli MF, Mecucci C. Acute myeloid leukemia carrying cytoplasmic/ mutated nucleophosmin (NPMc+ AML): Biologic and clinical features. Blood; 109: Breems DA, Löwenberg B. Acute myeloid leukemia and the position of autologous stem cell transplantation. Semin Hematol 2007; 44: Frassoni F, Labopin M, Powles, et al. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation. Effect of centre on outcome of bone-marrow transplantation for acute myeloid leukaemia. Lancet 2000; 355: Shaw BE, Gooley TA, Malkki M, et al. The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation. Blood 2007; 110: Eapen M, Rubinstein P, Zhang MJ, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: A comparison study. Lancet 2007; 369: HAEMATOPOIETIC STEM CELL TRANSPLANTATION 367

13 EBMT2008_1_21:EBMT :22 Pagina Flowers M, Parker P, Johnston L, et al. Comparison of chronic graft versus host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: Long term follow up of a randomized trial. Blood 2002; 100: Schmitz N, Eapen M, Horowitz MM, et al. Long-term outcome of patients given transplants of mobilized blood or bone marrow: A report from the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation. Blood 2006; 108: Gorin NC, Labopin M, Rocha, et al. European Cooperative Group for Blood and Marrow Transplantation Acute Leukaemia Working Party. Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukaemia: Influence of dose and stem cell source shows better outcome with rich marrow. Blood 2003; 102: Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med 2001; 344: Rocha V, Labopin M, Sanz G, et al. Transplants of Umbilical-Cord Blood or Bone Marrow from Unrelated Donors in Adults with Acute Leukemia. N Engl J Med 2004; 351: Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 2005; 105: Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: Aversa F, Terenzi A, Tabilio A, et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: A phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005; 23: Miller JS, Cooley S, Parham P, et al. Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GvHD) following unrelated donor allogeneic HCT. Blood 2007; 109: McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: Replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: Hegenbart U, Niederwieser D, Sandmaier BM, et al. Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol 2006; 24: Suciu S, Mandelli F, de Witte T, et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukaemia (AML) in first complete remission (CR1): An intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. Blood 2003; 102: Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukaemia. N Engl J Med 1995; 332: Burnett AK, Goldstone AH, Stevens R, et al. Randomised comparison of addition of 368 THE EBMT HANDBOOK 2008 REVISED EDITION

14 EBMT2008_1_21:EBMT :22 Pagina 369 CHAPTER 20 AML in adults autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: Results of MRC AML 10 trial. Lancet 1998; 351: Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia (ALL) the greatest benefit is achieved from a matched sibling allogeneic transplant in first complete remission (CR) and an autologous transplant is less effective than conventional consolidation/maintenance chemotherapy in ALL patients: Final results of the international ALL trial (MRC UKALL XII/ ECOG E2993). Blood 2007 Nov 29; [Epub ahead of print]. 25. Yanada M, Matsuo K, Emi N, Naoe T. Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission: A metaanalysis. Cancer 2005; 103: Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol 2005; 23: Mutiple Choice Questionnaire To find the correct answer, go to 1. For intermediate risk AML patients in CR1 what is the probability of relapsing after HLA identical sibling transplant? a) 30 40% b) 20 25% c) 40 50% d) 20% The recent meta-analysis of studies comparing chemotherapy, allo-transplant, and auto-transplant has shown better OS for allo-transplant in: a) Poor-risk cytogenetic patients b) Intermediate risk patients c) Favourable risk patients d) a+b Good risk AML is characterised by involvement of which of the following genes? a) FLT b) EV HAEMATOPOIETIC STEM CELL TRANSPLANTATION 369

15 EBMT2008_1_21:EBMT :22 Pagina 370 c) WT d) None of the above In RIC unrelated transplant the incidence of chronic GvHD at 180 days is: a) 20 25% b) 40 45% c) 10 20% d) 55 60% What is the current actuarial DFS at 3 years for AML patients autografted in CR1? a) 20 30% b) 70 80% c) 40 50% d) 10 20% THE EBMT HANDBOOK 2008 REVISED EDITION

16 EBMT2008_1_21:EBMT :22 Pagina 371 NOTES HAEMATOPOIETIC STEM CELL TRANSPLANTATION 371