Tra n s p l a n t a t i o n in A c u t e Myeloid Leukemia Tsila Zuckerman,
MD
a,b,
*, Jacob M. Rowe,
MD
a,b,c
KEYWORDS Acute myeloid leukemia Allogeneic stem cell transplantation Autologous stem cell transplantation Complete remission Genetic alterations KEY POINTS Allogeneic stem cell transplantation (allo-SCT) is recommended for patients with intermediate and unfavorable genetic risk. Allo-SCT is best performed in CR1. The chance of achieving CR2 is only 50%. Matched unrelated donor is increasingly used with no difference in the outcome compared with matched related donor (MRD). Alternative donors such as cord blood (CB) and haploidentical are being used, with encouraging data. There is no recommendation regarding the preferable stem cell source. Autologous SCT has a potent antileukemic effect mainly in favorable and intermediate-risk cytogenetic groups with reduced relapse and better leukemia-free survival compared with chemotherapy. Allo-SCT can safely be administered to fit older adults (aged 60–75 years), with results similar to those of younger adults. Further improvement in allo-SCT outcome includes assessment of minimal residual disease, graft engineering and incorporation of novel approaches (vaccines, adoptive T-cell transfer, and targeted therapy).
INTRODUCTION
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by somatic acquisition of genetic and epigenetic alterations in hematopoietic myeloid progenitors that perturb normal mechanisms of self-renewal, proliferation, and differentiation through accumulation of multistep cooperating mutations. Advance in molecular a Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 8 Haalia Hshnia Street, Bat Galim, Haifa 3525408, Israel; b The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Efron Street, P.O.B. 9649, Bat Galim, Haifa 31096, Israel; c Department of Hematology, Shaare Zedek Medical Center, 12 Shmuel Bait Street, Jerusalem 9102102, Israel * Corresponding author. Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, PO Box 9602, Haifa 31096, Israel. E-mail address: [email protected]
Hematol Oncol Clin N Am 28 (2014) 983–994 http://dx.doi.org/10.1016/j.hoc.2014.08.016 hemonc.theclinics.com 0889-8588/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
984
Zuckerman & Rowe
methods showed 23 commonly mutated genes and an average of 13 mutations per patient.1 The heterogeneity is not only interpatient but also intrapatient, with concomitant presence of genetically different leukemic subclones. This intraclonal genetic diversity reflects natural selection, leading to clonal evolution, disease progression, and relapse.2 In addition, it was recently shown that the disease may originate from a preleukemic hematopoietic progenitor harboring the DNMT3 or IDH2 mutations, which confers clonal expansion and with additional mutations can transform into AML.3 The importance of these findings is that to cure leukemia, we need to address not only the dominant clone at disease onset but also minor subclones that can lead to relapse. Until we better define the disease at the genetic level and its origin, AML treatment is intended to achieve complete remission (CR) with induction followed by postremission consolidation with either intensive chemotherapy, autologous stem cell transplantation (ASCT) or allogeneic stem cell transplantation (allo-SCT). This review focuses on the current role of transplantation in AML. INDICATIONS FOR STEM CELL TRANSPLANTATION IN THE GENOMIC ERA
Evaluation of AML prognosis shifted over the last 2 decades from clinical (or patient related) to a more powerful biological one, based on cytogenetic and molecular alterations present in DNA blasts at diagnosis (disease related). Although under constant revision, biological prognosis is subdivided into 3 main categories of favorable, intermediate, and poor risk.4 Integrated AML-related prognostic parameters are presented in Table 1. The recommended LeukemiaNet reporting on AML prognosis was developed based on large retrospective studies, such as the Medical Research Council Table 1 AML-related prognostic parameters Cytogenetic Markers
Molecular Markers
Clinical Factors
t (8;21) inv(16)/t (16;16) t (15;17)
Mutated CEBPA (double) Mutated NPM1 (without FLT3–ITD mutation)
Minimal residual disease negative
Enhanced Evi-1 expression MLL rearrangements FLT3–ITD mutation DNMT3A mutation BAALC expression ERG expression MN1 expression WT1 polymorphism BCR–ABL-positive
Increased age Increased WBC count Extramedullary disease No early CR Persistent minimal residual disease CD341 blasts Treatment-related AML
Adverse prognostic factors inv(3)/t (3;3) t (9;22) t (9;11) t (6;9) 5 or del (5q) 7 abn (17p) Complex karyotype Monosomal karyotype
Abbreviations: AML, acute myeloid leukemia; BAALC, gene encoding brain and acute leukemia cytoplasmic protein; CEBPA, gene encoding CCAAT/enhancer-binding protein; DNMT3A, gene encoding DNA (cytosine-5)-methyltransferase 3A; ERG, gene encoding transcriptional regulator ERG; Evi-1, MDS1 and EVI1 complex locus protein EVI1 (also known as ecotropic viral integration site 1); FLT3, fms-like tyrosine kinase receptor-3; ITD, internal tandem duplication; MLL, gene encoding histone-lysine N-methyltransferase MLL; MN1, gene encoding probable tumor suppressor protein MN1; NPM1, gene encoding nucleophosmin; WBC, white blood cell; WT1, gene encoding Wilms tumor protein. From Cornelissen JJ, Gratwohl A, Schlenk RF, et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol 2012;9:581; with permission.
Transplantation in Acute Myeloid Leukemia
(MRC).5 However, the postremission treatment was not stratified. The prognostic significance of these genetic alterations was recently evaluated in a large cohort of non– transplant treated patients. The classification clearly separates different genetic groups by outcome and hence can be used for stratification into different treatment groups in clinical trials.6 Integrated genetic profiling is a step forward in AML risk assessment. Using mutational analysis of 18 genes known to be involved in AML, Patel and colleagues7 managed to further refine the large intermediate-risk cytogenetic group into 3 significantly different prognostic subgroups based on molecular alterations, thus emphasizing the significance of coexistence and cooperation of different mutations in AML (Figs. 1–3). Without diminishing the importance of prognostic scores, the predictive value of postremission therapy should be cautiously interpreted, because it has not been prospectively tested in relation to postinduction treatment assignment. In addition, rapidly evolving knowledge and complexity of cooperating genetic alterations dissect patient populations into small cohorts, making analysis more complicated. Yet, available data, mainly from retrospective subanalyses of patients in large study groups that were genetically randomized to donor versus no donor, can aid in decision making. Patients with the FLT3-ITD mutation have a CR rate similar to that observed in patients with the wild-type after induction therapy; however, they have a higher relapse rate (RR). Most studies, although retrospective, reported that patients harboring the mutation had a better disease-free survival (DFS) and overall survival (OS) after allo-SCT compared with chemotherapy only.8,9 The beneficial effect of allo-SCT was restricted in some of the studies to patients having a low allelic ratio of mutated to wild-type FLT3 less than 0.8 or less than 0.5.10 In contrast, other studies failed to show an improved outcome after allo-SCT,11 whereas a large registry European Group For Blood and Marrow Transplantation (EBMT) study reported inferior outcome after allo-SCT in FLT3-positive versus FLT3-negative patients.12
Fig. 1. Mutational complexity of AML. (From Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012;366:1082; with permission.)
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Fig. 2. AML: revised risk classification: integrated genetic analysis. (From Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012;366:1085; with permission.)
Fig. 3. Revised risk stratification. (From Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012;366:1085; with permission.)
Transplantation in Acute Myeloid Leukemia
Monosomal karyotype is known to be associated with a poor outcome in AML. Whether it retains its prognostic effect after allo-SCT is not clear. Although some studies reported an improved outcome, especially when the disease was not associated with complex karyotype,13,14 others reported no or limited beneficial effect from a transplant.15 In the absence of prospective studies, a matched-pair analysis of prospectively treated patients can better clarify the role of allo-SCT in different cytogenetic groups. In a study by the German AML Cooperative Group (AMLCG99), allo-SCT (both from related and unrelated donors) had a significantly superior OS and decrease in RR compared with chemotherapy in both intermediate and unfavorable groups.16 Meta-analysis of the role of allo-SCT in AML can aid in decision making, because of the attainment of significant statistical power when data on many patients are combined. Studies by Koreth and colleagues17 including 6007 patients with AML in CR1 and by Cornelissen and colleagues18 with 1033 patients from 4 large intergroup trials showed improved leukemia-free survival (LFS) and OS in both poor-risk and intermediate-risk groups. When considering allo-SCT in AML, it is imperative to include covariates of the transplant itself, such as patient age, comorbidities, availability of a matched related or unrelated donor, and transplant regimen. These data accumulated in the LeukemiaNet recommendations on allo-SCT in AML patients in CR1 are presented in Table 2. STEM CELL TRANSPLANTATION IN FIRST COMPLETE REMISSION AND BEYOND
Given the risks associated with allo-SCT, it may be tempting to postpone the transplant to CR2. A large retrospective analysis of 667 relapsing patients treated in the AML Dutch-Belgian and the Swiss Groups, reported that only 46% of patients achieved CR2. Patients were stratified by duration of relapse-free interval after CR1, cytogenetic risk, age, and previous SCT, into 3 risk categories for outcome at relapse. Overall, the best outcome was achieved using allo-SCT (5-year OS of 26%–88% depending on the risk group). Yet, only 14% to 30% of relapsing patients received allo-SCT.19 Similar results were obtained in a large Japanese retrospective survey on the outcome of 1535 patients with AML who were treated with chemotherapy only before relapse. Sixty-six percent of patients relapsed and only half entered CR2. The achievement of CR2, using salvage allo-SCT, and a relapse-free interval of 1 year or longer, were independent prognostic factors for long-term outcome.20 A recent update from the MRC in the United Kingdom reported an outcome of 1271 patients, aged 16 to 49 years, who were treated with chemotherapy only in the MRC AML10, AML12, and AML15 trials, and subsequently relapsed. Only 55% of patients achieved CR2 and only 67% of them received an allo-SCT. The best long-term outcome was achieved with allo-SCT, with an OS of 42% in the transplanted group versus 16% in the nontransplanted group.21 A recent review by Forman and Rowe22 suggested that given the low probability of achieving CR2 and proceeding to alloSCT at that point as well as the dismal prognosis without allo-SCT, it is best to perform transplantation in CR1 according to previously suggested criteria. Moreover, allo-SCT is the only curative modality in CR2. TRANSPLANTATION FROM A MATCHED UNRELATED DONOR
Because the best long-term results in patients with intermediate-risk and poor-risk AML are achieved with administration of allo-SCT in CR1 and given that only 25% to 30% of patients have a matched related sibling, the question is whether the beneficial effect of SCT remains also with the use of matched unrelated donor (MUD) in
987
988
Risk of Relapse After Consolidation Approach AML Risk Groupb
AML Risk Assessmentc
Prognostic Scores for Nonrelapse Mortality that Would Indicate Allogeneic HSCT as Preferred Consolidation
Chemotherapy or AHSCT (%)
AlloHSCT (%)
EBMT Score
HCT–CI Score
Nonrelapse Mortality Risk (%)
Good
t (8;21) with WBC 20 Inv(16)/t (16;16) Mutated CEBPA (double allelic) Mutated NPM1 (No FLT3–ITD mutation) Early first CR and no minimal residual disease
35–40
15–20
NA (1)
NA (20 Cytogenetically normal (or with loss of X and Y chromosomes), WBC count 100 and early first CR (after first cycle of chemotherapy)
50–55
20–25
2
2
100 Cytogenetically abnormal
70–80
30–40
3–4
3–4
90
40–50
5
5
MD
a,b,
*, Jacob M. Rowe,
MD
a,b,c
KEYWORDS Acute myeloid leukemia Allogeneic stem cell transplantation Autologous stem cell transplantation Complete remission Genetic alterations KEY POINTS Allogeneic stem cell transplantation (allo-SCT) is recommended for patients with intermediate and unfavorable genetic risk. Allo-SCT is best performed in CR1. The chance of achieving CR2 is only 50%. Matched unrelated donor is increasingly used with no difference in the outcome compared with matched related donor (MRD). Alternative donors such as cord blood (CB) and haploidentical are being used, with encouraging data. There is no recommendation regarding the preferable stem cell source. Autologous SCT has a potent antileukemic effect mainly in favorable and intermediate-risk cytogenetic groups with reduced relapse and better leukemia-free survival compared with chemotherapy. Allo-SCT can safely be administered to fit older adults (aged 60–75 years), with results similar to those of younger adults. Further improvement in allo-SCT outcome includes assessment of minimal residual disease, graft engineering and incorporation of novel approaches (vaccines, adoptive T-cell transfer, and targeted therapy).
INTRODUCTION
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by somatic acquisition of genetic and epigenetic alterations in hematopoietic myeloid progenitors that perturb normal mechanisms of self-renewal, proliferation, and differentiation through accumulation of multistep cooperating mutations. Advance in molecular a Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 8 Haalia Hshnia Street, Bat Galim, Haifa 3525408, Israel; b The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Efron Street, P.O.B. 9649, Bat Galim, Haifa 31096, Israel; c Department of Hematology, Shaare Zedek Medical Center, 12 Shmuel Bait Street, Jerusalem 9102102, Israel * Corresponding author. Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, PO Box 9602, Haifa 31096, Israel. E-mail address: [email protected]
Hematol Oncol Clin N Am 28 (2014) 983–994 http://dx.doi.org/10.1016/j.hoc.2014.08.016 hemonc.theclinics.com 0889-8588/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
984
Zuckerman & Rowe
methods showed 23 commonly mutated genes and an average of 13 mutations per patient.1 The heterogeneity is not only interpatient but also intrapatient, with concomitant presence of genetically different leukemic subclones. This intraclonal genetic diversity reflects natural selection, leading to clonal evolution, disease progression, and relapse.2 In addition, it was recently shown that the disease may originate from a preleukemic hematopoietic progenitor harboring the DNMT3 or IDH2 mutations, which confers clonal expansion and with additional mutations can transform into AML.3 The importance of these findings is that to cure leukemia, we need to address not only the dominant clone at disease onset but also minor subclones that can lead to relapse. Until we better define the disease at the genetic level and its origin, AML treatment is intended to achieve complete remission (CR) with induction followed by postremission consolidation with either intensive chemotherapy, autologous stem cell transplantation (ASCT) or allogeneic stem cell transplantation (allo-SCT). This review focuses on the current role of transplantation in AML. INDICATIONS FOR STEM CELL TRANSPLANTATION IN THE GENOMIC ERA
Evaluation of AML prognosis shifted over the last 2 decades from clinical (or patient related) to a more powerful biological one, based on cytogenetic and molecular alterations present in DNA blasts at diagnosis (disease related). Although under constant revision, biological prognosis is subdivided into 3 main categories of favorable, intermediate, and poor risk.4 Integrated AML-related prognostic parameters are presented in Table 1. The recommended LeukemiaNet reporting on AML prognosis was developed based on large retrospective studies, such as the Medical Research Council Table 1 AML-related prognostic parameters Cytogenetic Markers
Molecular Markers
Clinical Factors
t (8;21) inv(16)/t (16;16) t (15;17)
Mutated CEBPA (double) Mutated NPM1 (without FLT3–ITD mutation)
Minimal residual disease negative
Enhanced Evi-1 expression MLL rearrangements FLT3–ITD mutation DNMT3A mutation BAALC expression ERG expression MN1 expression WT1 polymorphism BCR–ABL-positive
Increased age Increased WBC count Extramedullary disease No early CR Persistent minimal residual disease CD341 blasts Treatment-related AML
Adverse prognostic factors inv(3)/t (3;3) t (9;22) t (9;11) t (6;9) 5 or del (5q) 7 abn (17p) Complex karyotype Monosomal karyotype
Abbreviations: AML, acute myeloid leukemia; BAALC, gene encoding brain and acute leukemia cytoplasmic protein; CEBPA, gene encoding CCAAT/enhancer-binding protein; DNMT3A, gene encoding DNA (cytosine-5)-methyltransferase 3A; ERG, gene encoding transcriptional regulator ERG; Evi-1, MDS1 and EVI1 complex locus protein EVI1 (also known as ecotropic viral integration site 1); FLT3, fms-like tyrosine kinase receptor-3; ITD, internal tandem duplication; MLL, gene encoding histone-lysine N-methyltransferase MLL; MN1, gene encoding probable tumor suppressor protein MN1; NPM1, gene encoding nucleophosmin; WBC, white blood cell; WT1, gene encoding Wilms tumor protein. From Cornelissen JJ, Gratwohl A, Schlenk RF, et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol 2012;9:581; with permission.
Transplantation in Acute Myeloid Leukemia
(MRC).5 However, the postremission treatment was not stratified. The prognostic significance of these genetic alterations was recently evaluated in a large cohort of non– transplant treated patients. The classification clearly separates different genetic groups by outcome and hence can be used for stratification into different treatment groups in clinical trials.6 Integrated genetic profiling is a step forward in AML risk assessment. Using mutational analysis of 18 genes known to be involved in AML, Patel and colleagues7 managed to further refine the large intermediate-risk cytogenetic group into 3 significantly different prognostic subgroups based on molecular alterations, thus emphasizing the significance of coexistence and cooperation of different mutations in AML (Figs. 1–3). Without diminishing the importance of prognostic scores, the predictive value of postremission therapy should be cautiously interpreted, because it has not been prospectively tested in relation to postinduction treatment assignment. In addition, rapidly evolving knowledge and complexity of cooperating genetic alterations dissect patient populations into small cohorts, making analysis more complicated. Yet, available data, mainly from retrospective subanalyses of patients in large study groups that were genetically randomized to donor versus no donor, can aid in decision making. Patients with the FLT3-ITD mutation have a CR rate similar to that observed in patients with the wild-type after induction therapy; however, they have a higher relapse rate (RR). Most studies, although retrospective, reported that patients harboring the mutation had a better disease-free survival (DFS) and overall survival (OS) after allo-SCT compared with chemotherapy only.8,9 The beneficial effect of allo-SCT was restricted in some of the studies to patients having a low allelic ratio of mutated to wild-type FLT3 less than 0.8 or less than 0.5.10 In contrast, other studies failed to show an improved outcome after allo-SCT,11 whereas a large registry European Group For Blood and Marrow Transplantation (EBMT) study reported inferior outcome after allo-SCT in FLT3-positive versus FLT3-negative patients.12
Fig. 1. Mutational complexity of AML. (From Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012;366:1082; with permission.)
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Zuckerman & Rowe
Fig. 2. AML: revised risk classification: integrated genetic analysis. (From Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012;366:1085; with permission.)
Fig. 3. Revised risk stratification. (From Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012;366:1085; with permission.)
Transplantation in Acute Myeloid Leukemia
Monosomal karyotype is known to be associated with a poor outcome in AML. Whether it retains its prognostic effect after allo-SCT is not clear. Although some studies reported an improved outcome, especially when the disease was not associated with complex karyotype,13,14 others reported no or limited beneficial effect from a transplant.15 In the absence of prospective studies, a matched-pair analysis of prospectively treated patients can better clarify the role of allo-SCT in different cytogenetic groups. In a study by the German AML Cooperative Group (AMLCG99), allo-SCT (both from related and unrelated donors) had a significantly superior OS and decrease in RR compared with chemotherapy in both intermediate and unfavorable groups.16 Meta-analysis of the role of allo-SCT in AML can aid in decision making, because of the attainment of significant statistical power when data on many patients are combined. Studies by Koreth and colleagues17 including 6007 patients with AML in CR1 and by Cornelissen and colleagues18 with 1033 patients from 4 large intergroup trials showed improved leukemia-free survival (LFS) and OS in both poor-risk and intermediate-risk groups. When considering allo-SCT in AML, it is imperative to include covariates of the transplant itself, such as patient age, comorbidities, availability of a matched related or unrelated donor, and transplant regimen. These data accumulated in the LeukemiaNet recommendations on allo-SCT in AML patients in CR1 are presented in Table 2. STEM CELL TRANSPLANTATION IN FIRST COMPLETE REMISSION AND BEYOND
Given the risks associated with allo-SCT, it may be tempting to postpone the transplant to CR2. A large retrospective analysis of 667 relapsing patients treated in the AML Dutch-Belgian and the Swiss Groups, reported that only 46% of patients achieved CR2. Patients were stratified by duration of relapse-free interval after CR1, cytogenetic risk, age, and previous SCT, into 3 risk categories for outcome at relapse. Overall, the best outcome was achieved using allo-SCT (5-year OS of 26%–88% depending on the risk group). Yet, only 14% to 30% of relapsing patients received allo-SCT.19 Similar results were obtained in a large Japanese retrospective survey on the outcome of 1535 patients with AML who were treated with chemotherapy only before relapse. Sixty-six percent of patients relapsed and only half entered CR2. The achievement of CR2, using salvage allo-SCT, and a relapse-free interval of 1 year or longer, were independent prognostic factors for long-term outcome.20 A recent update from the MRC in the United Kingdom reported an outcome of 1271 patients, aged 16 to 49 years, who were treated with chemotherapy only in the MRC AML10, AML12, and AML15 trials, and subsequently relapsed. Only 55% of patients achieved CR2 and only 67% of them received an allo-SCT. The best long-term outcome was achieved with allo-SCT, with an OS of 42% in the transplanted group versus 16% in the nontransplanted group.21 A recent review by Forman and Rowe22 suggested that given the low probability of achieving CR2 and proceeding to alloSCT at that point as well as the dismal prognosis without allo-SCT, it is best to perform transplantation in CR1 according to previously suggested criteria. Moreover, allo-SCT is the only curative modality in CR2. TRANSPLANTATION FROM A MATCHED UNRELATED DONOR
Because the best long-term results in patients with intermediate-risk and poor-risk AML are achieved with administration of allo-SCT in CR1 and given that only 25% to 30% of patients have a matched related sibling, the question is whether the beneficial effect of SCT remains also with the use of matched unrelated donor (MUD) in
987
988
Risk of Relapse After Consolidation Approach AML Risk Groupb
AML Risk Assessmentc
Prognostic Scores for Nonrelapse Mortality that Would Indicate Allogeneic HSCT as Preferred Consolidation
Chemotherapy or AHSCT (%)
AlloHSCT (%)
EBMT Score
HCT–CI Score
Nonrelapse Mortality Risk (%)
Good
t (8;21) with WBC 20 Inv(16)/t (16;16) Mutated CEBPA (double allelic) Mutated NPM1 (No FLT3–ITD mutation) Early first CR and no minimal residual disease
35–40
15–20
NA (1)
NA (20 Cytogenetically normal (or with loss of X and Y chromosomes), WBC count 100 and early first CR (after first cycle of chemotherapy)
50–55
20–25
2
2
100 Cytogenetically abnormal
70–80
30–40
3–4
3–4
90
40–50
5
5
