REVIEW URRENT C OPINION
Is it time to change conventional consolidation chemotherapy for acute myeloid leukemia in CR1? Ofir Wolach and Richard M. Stone
Purpose of review Choosing the most appropriate postremission therapy (PRT) for a patient with acute myeloid leukemia (AML) in first complete remission remains a challenging task. Factors such as risk for disease relapse, nonrelapse mortality associated with different PRT approaches, donor availability, prospects for salvage should disease relapse, and patient preference all affect PRT choice. Recent findings New genetic markers refine AML risk stratification and identify patients within the ‘classical’ risk groups who may benefit from transplant-based or chemotherapy-based PRT. The use of minimal residual disease in first remission to guide PRT choice and the application of novel, targeted therapies have the potential to alter PRT approaches across AML risk groups. The advent of alternative donor sources, use of reduced intensity regimens, and improved supportive care all affect the availability and safety of transplant-based PRT and challenge the relevance of the older legacy ‘donor/no-donor’ genetically randomized trials. Summary Genetic risk assessment, monitoring of minimal residual disease in first remission, use of targeted agents, and the newer transplant strategies all have the potential to ‘personalize’ PRT choice in the AML patient. The clinical value of these novel interventions awaits validation in prospective, risk-adapted clinical trials. Keywords acute myeloid leukemia, allogeneic stem cell transplant, first remission, postremission therapy
INTRODUCTION The principles that guide the therapeutic approach to younger patients with acute myeloid leukemia (AML) have changed little over the years: high-dose chemotherapy to induce remission and restore normal hematopoiesis followed by postremission therapy (PRT) directed at elimination of disease [1]. Four decades since ‘3 þ 7’ induction therapy with daunorubicin and cytarabine was first introduced [2], it is still regarded (with minor alterations) as a standard induction regimen. How to manage the patient once first complete remission is attained is a matter of ongoing controversy that can be essentially summarized by the question: Who should get a transplant in first remission? A clear answer to this question is not easy to give for several reasons: (1) AML encompasses a heterogeneous group of diseases that differ in molecular pathophysiology [3]. The prognostic significance of specific mutations as well as the effect of mutational patterns are an ongoing focus of research [4]. To
date, internal tandem duplications in the fms-like tyrosine kinase 3 gene (FLT3-ITD) and mutations in nucleophosmin1 (NPM1) and in CCAAT/enhancer-binding protein alpha (CEBPA) are the ones most likely to affect PRT [5,6]. Targeted interventions against recently discovered (driver) mutations may affect PRT choice in the future. (2) Predicting relapse risk in the specific patient remains a challenge. The advent of techniques that assess minimal residual disease (MRD) in first remission are promising and were shown to have prognostic value [7,8], but still need to be
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Correspondence to Richard M. Stone, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA. Tel: +1 617 632 2214; fax: +1 617 632 2933; e-mail: [email protected] Curr Opin Hematol 2015, 22:123–131 DOI:10.1097/MOH.0000000000000119
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KEY POINTS The choice of the most appropriate postremission approach for the AML patient in first remission is complex and should take into account several factors including disease-related factors (relapse risk), patientrelated factors (performance status, patient preference), and transplant-related factors (donor availability, predicted NRM). The abundance of new genetic prognostic markers may identify patients within the ‘classic’ cytogenetic risk group for which different postremission approaches may be advisable. Monitoring minimal residual disease in first remission holds promise as a tool to direct postremission therapy. The advent of novel, targeted approaches may affect choice of postremission intervention (e.g. dasatinib in core binding factor leukemia). The clinical value of these novel interventions awaits validation in prospective, risk-adapted clinical trials.
validated in the context of prospective PRT decision analysis. (3) Most prospective comparisons of allogeneic stem cell transplant (alloSCT) and chemotherapy in first remission via sibling donor-based allocation were done in an era when matched related sibling donors and myeloablative conditioning were applied. Better supportive care, the use of matched unrelated donors (MUDs) as well as alternative donor sources and reduced intensity preparative regimens all challenge the relevance of the older data sets [9–14]. Robust, evidence-based data concerning the effect of these changes on PRT choice are needed.
RISK-ADAPTED APPROACH TO POSTREMISSION THERAPY: A MOVING TARGET Diagnostic cytogenetics is of cardinal importance in predicting remission, risk of relapse, and survival in patients treated for AML [15–17]. Patients currently are stratified into three prognostic groups based on cytogenetics. Those harboring core binding factor (CBF) translocations [inv16, t(8;21)] have a predicted long-term survival of approximately 65%. Patients with poor outcome include patients with deletions of the long arms of chromosome 5 or 7, complex karyotypes (3 chromosomal abnormalities), and translocations involving the EVI1 gene at 3q26. Within this adverse group, patients with monosomal karyotype do extremely poorly with long-term survival well under 10% [18,19]. The poor outcome of patients with monosomal karyotype probably stems from its association with p53 loss of function predicting chemo-resistant disease [20]. The intermediate-risk group mainly consists of patients with normal cytogenetics (40–50% of all AML patients) who have an approximate 40% likelihood for long-term survival. In this group, the presence of mutations in NPM1 with negative FLT3-ITD status or bi-allelic mutated CEBPA confers outcomes comparable to those of patients with CBFAML [21] (Table 1). Every large cooperative trial (mostly done in the last millennium) that assessed the value of alloSCT in first remission failed to demonstrate an overall survival (OS) advantage for alloSCT, mainly because the clear advantage in terms of reducing relapse rates was offset by the much higher treatment-related mortality [22–29]. These trials employed ‘genetic randomization’, meaning that patients with a matched related sibling were allocated to alloSCT,
Table 1. Estimated outcomes of patients with acute myeloid leukemia based on integrated genetic and cytogenetic risk Risk group
Cytogenetics/genetics
Approximate 4-year OS
Approximate prevalence
Very high
Monosomal karyotypea
10%
6%
High
Complex karyotype
20%
12%
35%
25%
Other unfavorable cytogenetics Intermediate
Normal cytogenetics (nonfavorable genetic pattern) Other nonfavorable and nonadverse cytogenetics
Favorable Very favorable
Inv16 or t(8;21) with c-KITmut
40%
5%
Normal cytogenetics with FLT3-ITDneg/NPM1pos
50%
25%
Normal cytogenetics with double CEBPA mutations
60%
5%
Inv16 or t(8;21) with c-KITWT
65%
10%
t(15;17)
85%
12%
CEBPA, CCAAT/enhancer-binding protein alpha; FLT3-ITD, fms-like tyrosine kinase 3 gene; NPM1, nucleophosmin1; OS, overall survival. Previously published. Source [1]. a Usually associated with P53 alterations.
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whereas others received a non-alloSCT PRT [with a second randomization to intensive chemo vs. autologous transplant (autoSCT) in some cases]. Subgroup analysis depicted a consistent survival benefit for alloSCT in the adverse-risk group; no clear conclusion as to the best PRT in intermediate and favorable groups could be drawn. For example, in the EORTC/GIMEMA AML10 trial, alloSCT was found to significantly improve survival in the adverse-risk group (4-year OS of 50 vs. 29%; more so in younger patients), but not in the favorable or intermediate groups [28]. However, the MRC trial suggested benefit of alloSCT only in intermediate-risk patients [30]. Slovak et al. analyzed the effect of cytogenetics on outcome in 412 younger newly diagnosed patients with AML in first remission enrolled onto a SWOG/ECOG trial; multivariate analysis showed that alloSCT was better than chemotherapy or autoSCT in patients with adverse cytogenetics. Intermediate-risk patients seemed to benefit more from chemotherapy. In this analysis, and in contrast to most other studies, favorable-risk patients fared better with autoSCT or alloSCT as compared to chemotherapy alone [17]. Several meta-analyses attempted to more clearly guide risk-adapted PRT choice [24,31,32]. In the largest of these studies, Koreth et al. [31] analyzed 24 trials (including 6007 patients) and demonstrated a significant OS advantage for alloSCT in first remission for patients with intermediate and high risk, but not for those with favorable-risk AML. Matched pairs analysis of patients enrolled onto the German AMLCG99 trial was recently reported [33 ]. Matching was done prospectively and patients were matched in similar time frames within the study, thus controlling for trends in supportive care and practice that could influence outcome. One hundred and eighty-five matched pairs of newly diagnosed AML patients younger than 60 years were controlled for age, AML type, cytogenetic risk and time in complete remission. Patients were not prospectively matched for FLT3 and NPM1 status, although these genetic mutations were equally prevalent in both groups. Patients with intermediate risk and a matched-sibling donor and those with high-risk disease with a matched-sibling donor or MUD were offered transplant in first remission. OS at 7 years was significantly better for patients in the alloSCT arm (58 vs. 46%) as was relapse-free survival (RFS; 52 vs. 33%). Subgroup analysis suggested that the benefit of alloSCT was more pronounced in patients with adverse risk, those with intermediate risk and abnormal cytogenetics, and in early responders (based on day 15 marrow). In contrast to prior studies [28,30], patients 45–59 years had most benefit from alloSCT, possibly reflecting better &
supportive care and age-appropriate conditioning regimens.
IS HIGH-DOSE CYTARABINE THE RIGHT CHOICE FOR ALL CYTOGENETICALLY FAVORABLE PATIENTS: THE CASE OF CORE BINDING FACTOR LEUKEMIA The pivotal CALGB 8525 trial demonstrated the superiority of repetitive cycles of high-dose cytarabine (HiDAC) for consolidation therapy compared with lower doses [34]. Subgroup analysis demonstrated that most of the benefit from HiDAC was observed in patients with CBF-AML (complete remission rate of 78% and 5-year OS of 64%) [35]. Additional analyses underscored the importance of 3–4 cycles of HiDAC consolidation (as opposed to fewer cycles) in attaining maximal benefit from cytarabine [36,37], and suggested that RAS-mutated patients might be in the likely-to-benefit group [38]. One-third to one-half of patients with so-called ‘favorable-risk’ leukemia experience disease relapse with a HiDAC-based PRT approach, but are there patients with CBF-AML who may benefit from a transplant-based approach? Risk factors for treatment failure in CBF leukemia include older age [39–41], higher white blood cell count at diagnosis [39,42,43], therapy-related disease [44,45], lower platelet counts [40,43], non-white ethnicity [40], and loss of Y chromosome [43] (the latter two only for 8;21). Deletion of the long arm of chromosome 9 and trisomy 22 were associated with favorable outcome in patients with (8;21) and inv16, respectively [40,43]. However, adverse risk cannot be assumed to be an indication for alloSCT without prospective data. In one retrospective study, the outcome of 132 patients with CBF-AML treated with chemotherapy within German cooperative trials was compared with that of 118 patients with CBF-AML who had alloSCT and whose information was extracted from the CIBMTR registry. Patients with loss of sex chromosome had similar outcome, regardless of PRT employed, whereas patients without such a chromosome loss fared less with alloSCT [46]. Activating mutations in KIT are found in approximately one-third of patients with CBF-AML and may occur in exon 17 (encoding the activation loop of the receptor) or exon 8 (in the extracellular domain). KIT mutations are generally regarded as indicators of poor prognosis, although data are not consistent across studies and are more robust for (8;21) [47]. According to the latest National Comprehensive Cancer Network guidelines, the presence of KIT mutation in CBF will render a patient intermediate risk [6] such that more aggressive PRT or clinical trial should be considered. Since KIT mutations
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seem to drive proliferation and affect outcome, and KIT is highly expressed even in nonmutated CBF-AML patients [47], inhibition of KIT may be an attractive therapeutic target. Additional genetic lesions (FLT3-ITD, FLT3-TKD, NRAS, KRAS, and CBL), specific gene expression profiles, and overexpression of BAALC and MN1 [39,48–51] may affect outcome, but their effect on PRT choice is yet to be defined. In pediatric acute lymphoblastic leukemia, the presence of MRD after induction is a poor prognostic sign and often considered an indication for alloSCT. What is the situation in CBF-AML? Jourdan et al. [52] recently reported on 198 CBF-AML patients (ages 18–60) who were randomly assigned to standard vs. intensive induction followed by three cycles of HiDAC in a multicenter French trial. MRD was serially, prospectively, and centrally measured by quantitative PCR; less than 3-log MRD reduction at the end of first consolidation emerged as the sole predictor of relapse in multivariate analysis. MRD and MRDþ corresponded to a cumulative incidence of relapse and RFS at 36 months of 22 vs. 54% and 73 vs. 44%, respectively. Of 278 patients with CBF-AML enrolled in the MRC AML-15 trial, MRD at different time points after induction therapy and during follow-up was predictive of relapse [53]. In a trial including 137 patients with CBF (8;21), AML treated with standard induction followed by two cycles of intermediate-dose cytarabine, PCR-based MRD after second consolidation (less vs. more than 3-log reduction) was used to allocate patients to chemotherapy/autoSCT PRT or alloSCT (matched sibling, MUD, or haploidentical). This risk-adapted approach (actually employed in 69 of 116 patients) was associated with cumulative incidence of relapse of 15% at 5 years (22% in highrisk patients receiving alloSCT and 5% in low-risk patients receiving chemo/autoSCT), disease-free survival of 74.7% at 5 years (61.7% in high-risk and 94.7% in low-risk patients), and OS of 82.7% at 5 years (71.6% in high-risk and 100% in low-risk patients). Of note, KIT mutations were more frequent in the high-risk MRD group (55 vs. 17.6%) and alloSCT showed only a trend towards reducing relapse in this subgroup (although numbers were small) [54 ]. The same group later demonstrated that MRD rather than KIT status can predict post-transplant relapse and can be used to direct preemptive interventions such as donor lymphocyte infusions [55]. Is the long-used HiDAC the optimal chemo for PRT of CBF-AML? This therapy can be associated with significant morbidity and mortality; in the original study by Mayer et al. [34] (in which onethird of patients were over 60 years), 71% of patients required hospitalization after therapy, 12% suffered &
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severe CNS toxicities, and 5% died in complete remission. From a pharmacokinetic standpoint, intracellular saturation of cytarabine’s cytotoxic metabolite, ara-CTP, occurs at drug blood levels that are much lower than those achieved by HiDAC [56,57]. Further escalating the PRT HiDAC dose (beyond the standard Mayer 18 g/m2) did not result in improved efficacy [58]. Moreover, clinical trials that randomized patients to higher dose vs. intermediate doses of cytarabine (in the range of 1–2 g/m2) for PRT showed comparable results, suggesting that HiDAC at 3 g/m2 may be too high [59–62]. The addition of fludarabine was previously suggested to sensitize cells to the cytotoxic effects of cytarabine by inducing the enzyme deoxycytidine kinase [63]; some encouraging results were observed when fludarabine was added to induction and PRT cycles, although this approach has not yet been compared to standard HiDAC [64,65]. Interestingly, in the MRC-AML 15 trial, patients with favourablerisk AML did exceptionally well when FLAG-based induction (fludarabine, cytarabine, and G-CSF) was followed by cytarabine-based consolidation (8-year OS 95%) [62]. The addition of novel and effective agents to therapy of patients with CBF-AML could further change the PRT equation, perhaps improving the prognosis in difficult subsets, thereby making it less likely that any patient will need transplant-based PRT. Among these interventions, adding a tyrosine kinase inhibitor or gemtuzumab ozogamycin (Myelotarg) has the most current potential. A phase II trial (CALGB 10801) assessed the safety and efficacy of adding the KIT inhibitor dasatinib (100 mg/day) to chemotherapy, followed by dasatinib maintenance in patients with CBF-AML (n ¼ 61, age 19–85 years). Younger patients (n ¼ 45) experienced a 93% complete remission rate, and disease-free survival and OS at 2 years were 74 and 96%, respectively. The KIT mutation status did not seem to affect outcome [66]. Another trial found that dasatinib did not prevent overt relapse or progression when given preemptively to patients with CBF-AML and positive MRD [67]. An ongoing phase III trial conducted by the German AMLSG may help to determine if including dasatinib in the therapy of CBF-AML improves outcome. Several phase III RCTs of chemotherapy gemtuzumab ozogamycin in unselected AML yielded inconclusive efficacy results possibly related to different dosing schedules of gemtuzumab ozogamycin and variability in the patients studied, but subgroup analyses suggested that the CBF-AML group had very good outcomes if gemtuzumab ozogamycin was received. A recent meta-analysis consolidated data from five trials and 3325 patients. Volume 22 Number 2 March 2015
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Although no differences in complete remission rates were noted, a significant OS advantage and a reduction in relapse rates were noted in gemtuzumab ozogamycin arms. Patients with favorable risk benefited most from gemtuzumab ozogamycin, followed by patients with intermediate-risk disease [68]. In summary, ‘one size’ PRT does not fit all in CBF-AML which is more heterogeneous than previously appreciated. We recommend that all CBFAML patients should be screened for KIT mutation. Patients without KIT mutation should get standard HiDAC PRT. All, but particularly those patients whose leukemias harbor mutations, should be considered for clinical trial in which agents such as dasatinib or gemtuzumab ozogamycin are included. Despite the nonavailability of real data, KITmutated CBF-AML patients would at least be strongly considered for transplant-based PRT. Although using the presence of postinduction MRD as an indication for transplant-based PRT
seems promising, we await well-designed, riskadapted trials to test this approach. MRD assessment may also serve as a tool to assess response to new agents and thus guide the choice of PRT (Fig. 1).
PATIENTS WITH INTERMEDIATE-RISK ACUTE MYELOID LEUKEMIA IN FIRST REMISSION: ONGOING CONTROVERSY The approach to PRT in patients with intermediaterisk AML is still a matter of ongoing controversy. Subgroup analysis from the large ‘genetically randomized’ studies yielded conflicting results. The MRC AML 10 analysis reported an OS benefit with alloSCT in these patients [30], the SWOG/ ECOG study suggested chemotherapy performs best in terms of survival [17], and the EORTC/GIMEMA AML 10 and HOVON/SAKK analyses both showed no difference in OS between the different PRT approaches [24,28]; however, the chemotherapybased PRT strategies were nonuniform and
AML in first remissiona
Favorable risk cytogenetics neg
Normal karyotype with FLT3-ITD or double allelic CEBPA
pos
Adverse risk cytogenetics
Normal karyotype with non-favorable genetics
/NPM1
Intermediate risk cytogenetics
High risk features?b No
3-4 cycles of HiDAC
Monosomal karyotype/p53 alteration? No
Yes
Consider AlloSCT within clinical trial
AlloSCT from matched-related or MUD
Yes
alloSCTc
Clinical trial
Clinical trial
AlloSCTc
Targeted therapy (dasatinib, GO) within clinical trial FLT3-ITD allele burden to guide PRT? MRD directed therapy?
Integrated genetic profiling to guide PRT?
AlloSCT from alternative donor sources?
Novel targeted approaches (FLT3 inhibitors)? a
Excluding patients with acute promyelocytic leukemia.
b
For core binding factor leukemia: c-KIT mutation. Additional risk factors that may affect PRT allocation include: WBC
count>20X109/L at presentation, older age at presentation (>35-50 years), therapy related CBF-AML and various secondary genetic alterations (see text). c
Alternative donor sources should be considered if predicted relapse risk very high (>80%) and expected NRM reasonable (0.5) may be those that benefit most from a transplant-based approach [78,79 ]. The role of FLT3 inhibitors in FLT3-positive leukemias and the impact of adding such targeted therapy on PRT choice are actively being investigated. The choice of initial PRT therapy in AML must also consider the effect of salvage after relapse postCR1 chemo vs. alloSCT. An analysis of three MRC trials in younger AML patients (16–49 years) revealed that 5-year survival for patients that relapsed after transplant or no-transplant in CR1 was 7 and 19%, respectively. Among the 1271 patients who relapsed after not being transplanted in CR1, 55% achieved a second remission (82, 54, and 27% in the favorable, intermediate, and adverse groups, respectively), corresponding to a 5-year survival of 32, 17, and 7%, in the favorable, intermediate, and adverse groups, respectively. Patients who were transplanted in second remission had better outcomes than those treated with more &
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chemotherapy (42 vs. 16% at 5 years). An analysis based at least in part on resource utilization suggested that transplant should be deferred until second remission in intermediate-risk patients since this approach would result in similar survival to transplanting all patients [80]. On the basis of the available data, we refer most patients with intermediate-risk disease to alloSCT if a matched donor (related or unrelated [6,12,81]) exists and if patient’s predicted nonrelapse mortality (NRM) is reasonable. Patients who have normal cytogenetics and a ‘favorable’ genetic pattern (FLT3-ITDneg/NPM1pos or those with double allelic CEBPA mutations) receive HiDAC-based PRT [21]. Integrating novel genetic risk factors and MRD into decision analysis awaits further prospective assessment (Fig. 1).
ADVERSE-RISK ACUTE MYELOID LEUKEMIA: DEFINING THE WORST OF THE WORST Patients with adverse cytogenetics have relatively low remission rates and short-lived responses. Virtually all donor/no-donor trials suggest alloSCT in first remission; results are clearly better than for chemo-based PRT, but far from optimal (Table 1) [17,24,28,31,32,33 ]. Within this difficult-to-treat group of patients, those with a monosomal karyotype, defined by the presence of a least two autosomal monosomies or a single autosomal monosomy (excluding loss of sex chromosome) in combination with at least one structural abnormality, constitute the most inferior subgroup. Monosomal karyotype occurs in 10–15% of patients with AML and is more frequent in older age and in the context of secondary leukemia [82]. Analysis of consecutive HOVON/SAKK trials demonstrated a 4-year OS of only 4% (n ¼ 184) as compared to 26% (n ¼ 525) in patients with nonmonosomal karyotype adverse abnormalities [18]. The resistant nature of monosomal karyotype-AML was confirmed in analysis of SWOG (4-year OS of 3%; age 16–88 years) and German (4-year OS of 9%; age 16–85 years) data sets [19,83]. P53 alterations are common in patients with monosomal karyotype (80% in one study [20]). These alterations may account for the poor outcome based on chemoresistance that is perhaps associated with an increase in multidrug resistance pump activity [84]. Moreover, adverse outcome after alloSCT in myelodysplastic syndrome stems from the presence of p53 mutations rather than from the associated complex karyotype [85]; such patients should be considered for clinical trials with novel, targeted therapies (Fig. 1). &
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Postremission therapy for myeloid leukemia Wolach and Stone
Whether alloSCT benefits poor-risk patients is not clear. Monosomal karyotype predicts inferior outcome after alloSCT as compared to other adverse-risk patients [86], and may be so poor as to not yield benefit even in young patients [19]. However, a retrospective analysis from Seattle demonstrated a 4-year OS of 30% among 35 (pediatric and older) patients with monosomal karyotype in first remission; no survivors were noted in the nontransplant control group [87]. A comparative analysis from HOVON/SAKK reported on 107 patients (age 15–60 years) with monosomal karyotype in first remission; alloSCT was performed in 45 patients, chemotherapy in 48 patients, and autoSCT in 14. A survival benefit was noted for patients who were consolidated with alloSCT (matched related or MUD) vs. all other patients with 5-year OS and RFS of 19 vs. 9% (P ¼ 0.02) and 17 vs. 7% (P ¼ 0.003), respectively [88]. In patients with adverse prognosis, a more liberal approach to donor source is frequently exercised because of the grave outcome that is associated with a nontransplant approach. Several retrospective analyses demonstrated comparable outcomes for patients after matched-related or MUD alloSCT [9,12,13,81,89,90]. Alternative donors (partially mismatched unrelated donors, umbilical cord blood, or haploidentical donors) are increasingly utilized in the setting of high-risk disease in which treatment failure with non-alloSCT PRT is felt to overshadow the higher complication rate and NRM associated with these donor sources. Several uncontrolled studies suggest that alternative donor sources may be beneficial in the high-risk setting [14,91– 93]. In a recent consensus statement from the European LeukemiaNet, alloSCT from an alternative donor was endorsed in patients with more than 80% relapse risk who lack a matched-related or MUD and who have an anticipated nonrelapse mortality of less than 35% [94].
CONCLUSION Choosing the most appropriate PRT approach for a patient in first complete remission remains a challenging task. The main factors that should affect decision analysis include the risk for disease relapse (based on clinical presentation, cytogenetics, and mutations), the competing risk of NRM, donor availability, the prospects for successful salvage should patient relapse and of course patient preference. The abundance of prognostic information that stems from molecular studies adds another level of complexity in correctly predicting the risk of relapse. The rate at which new prognostic information is introduced to the clinic is extraordinary,
but the precise role of most of these data awaits validation in prospective, risk-adapted clinical trials. The same applies for the application of MRD monitoring in first remission. The advent of novel, targeted therapies is another consequence of the growing understanding of the pathways (genetic and others) that drive leukemia. These agents may also impact the decision on PRT. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest R.M.S. – BMS, ad hoc consultant; O.W. – none.
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TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 2012; 119:2114– 2121. 21. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358:1909–1918. 22. Burnett AK, Goldstone AH, Stevens RM, et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children’s Leukaemia Working Parties. Lancet 1998; 351:700–708. 23. Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998; 339:1649–1656. 24. Cornelissen JJ, van Putten WL, Verdonck LF, et al. Results of a HOVON/ SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood 2007; 109:3658–3666. 25. Harousseau JL, Cahn JY, Pignon B, et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM). Blood 1997; 90:2978–2986. 26. Keating S, de Witte T, Suciu S, et al. The influence of HLA-matched sibling donor availability on treatment outcome for patients with AML: an analysis of the AML 8A study of the EORTC Leukaemia Cooperative Group and GIMEMA. European Organization for Research and Treatment of Cancer. Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto. Br J Haematol 1998; 102:1344–1353. 27. Reiffers J, Stoppa AM, Attal M, et al. Allogeneic vs. autologous stem cell transplantation vs. chemotherapy in patients with acute myeloid leukemia in first remission: the BGMT 87 study. Leukemia 1996; 10:1874–1882. 28. 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 leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. Blood 2003; 102:1232–1240. 29. Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 1995; 332:217–223. 30. Burnett AK, Wheatley K, Goldstone AH, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol 2002; 118:385– 400. 31. Koreth J, Schlenk R, Kopecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. J Am Med Assoc 2009; 301:2349–2361. 32. 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 meta-analysis. Cancer 2005; 103:1652–1658. 33. Stelljes M, Krug U, Beelen DW, et al. Allogeneic transplantation versus & chemotherapy as postremission therapy for acute myeloid leukemia: a prospective matched pairs analysis. J Clin Oncol 2014; 32:288–296. In this German study, a prospective paired match analysis confirms a survival advantage for alloSCT in CR1 in intermediate and high-risk AML patients. 34. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994; 331:896–903. 35. Bloomfield CD, Lawrence D, Byrd JC, et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 1998; 58:4173–4179. 36. Byrd JC, Dodge RK, Carroll A, et al. Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered. J Clin Oncol 1999; 17:3767–3775.
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37. Byrd JC, Ruppert AS, Mrozek K, et al. Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): results from CALGB 8461. J Clin Oncol 2004; 22:1087–1094. 38. Neubauer A, Maharry K, Mrozek K, et al. Patients with acute myeloid leukemia and RAS mutations benefit most from postremission high-dose cytarabine: a Cancer and Leukemia Group B study. J Clin Oncol 2008; 26:4603– 4609. 39. Hoyos M, Nomdedeu JF, Esteve J, et al. Core binding factor acute myeloid leukemia: the impact of age, leukocyte count, molecular findings, and minimal residual disease. Eur J Haematol 2013; 91:209–218. 40. Marcucci G, Mrozek K, Ruppert AS, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol 2005; 23:5705–5717. 41. Delaunay J, Vey N, Leblanc T, et al. Prognosis of inv(16)/t(16;16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup. Blood 2003; 102:462–469. 42. Nguyen S, Leblanc T, Fenaux P, et al. A white blood cell index as the main prognostic factor in t(8;21) acute myeloid leukemia (AML): a survey of 161 cases from the French AML Intergroup. Blood 2002; 99:3517–3523. 43. Schlenk RF, Benner A, Krauter J, et al. Individual patient data-based metaanalysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol 2004; 22:3741–3750. 44. Borthakur G, Lin E, Jain N, et al. Survival is poorer in patients with secondary core-binding factor acute myelogenous leukemia compared with de novo core-binding factor leukemia. Cancer 2009; 115:3217–3221. 45. Gustafson SA, Lin P, Chen SS, et al. Therapy-related acute myeloid leukemia with t(8;21) (q22;q22) shares many features with de novo acute myeloid leukemia with t(8;21)(q22;q22) but does not have a favorable outcome. Am J Clin Pathol 2009; 131:647–655. 46. Schlenk RF, Pasquini MC, Perez WS, et al. HLA-identical sibling allogeneic transplants versus chemotherapy in acute myelogenous leukemia with t(8;21) in first complete remission: collaborative study between the German AML Intergroup and CIBMTR. Biol Blood Marrow Transplant 2008; 14:187–196. 47. Paschka P, Dohner K. Core-binding factor acute myeloid leukemia: can we improve on HiDAC consolidation? Hematology Am Soc Hematol Educ Program 2013; 2013:209–219. 48. Allen C, Hills RK, Lamb K, et al. The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in corebinding factor acute myeloid leukemia. Leukemia 2013; 27:1891–1901. 49. Bullinger L, Rucker FG, Kurz S, et al. Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia. Blood 2007; 110:1291–1300. 50. Luck SC, Russ AC, Botzenhardt U, et al. Deregulated apoptosis signaling in core-binding factor leukemia differentiates clinically relevant, molecular marker-independent subgroups. Leukemia 2011; 25:1728–1738. 51. Luck SC, Russ AC, Du J, et al. KIT mutations confer a distinct gene expression signature in core binding factor leukaemia. Br J Haematol 2010; 148:925– 937. 52. Jourdan E, Boissel N, Chevret S, et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood 2013; 121:2213–2223. 53. Yin JA, O’Brien MA, Hills RK, et al. Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial. Blood 2012; 120:2826–2835. 54. Zhu HH, Zhang XH, Qin YZ, et al. MRD-directed risk stratification treatment & may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial. Blood 2013; 121:4056–4062. This is one of the only trials to use minimal residual disease as a prospective tool for PRT allocation in CBF-AML. 55. Wang Y, Wu DP, Liu QF, et al. RUNX1/RUNX1T1-based MRD-monitoring early after allogeneic transplantation rather than c-KIT mutations in adult t(8;21) AML allows further risk stratification. Blood 2014. [Epub ahead of print] 56. Plunkett W, Liliemark JO, Adams TM, et al. Saturation of 1-beta-D-arabinofuranosylcytosine 5’-triphosphate accumulation in leukemia cells during highdose 1-beta-D-arabinofuranosylcytosine therapy. Cancer Res 1987; 47:3005–3011. 57. Jamieson GP, Snook MB, Wiley JS. Saturation of intracellular cytosine arabinoside triphosphate accumulation in human leukemic blast cells. Leuk Res 1990; 14:475–479. 58. Schaich M, Rollig C, Soucek S, et al. Cytarabine dose of 36 g/m(2) compared with 12 g/m(2) within first consolidation in acute myeloid leukemia: results of patients enrolled onto the prospective randomized AML96 study. J Clin Oncol 2011; 29:2696–2702. 59. Miyawaki S, Ohtake S, Fujisawa S, et al. A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of highdose cytarabine alone in postremission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study. Blood 2011; 117:2366–2372. 60. Lowenberg B. Sense and nonsense of high-dose cytarabine for acute myeloid leukemia. Blood 2013; 121:26–28.
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Postremission therapy for myeloid leukemia Wolach and Stone 61. Lowenberg B, Pabst T, Vellenga E, et al. Cytarabine dose for acute myeloid leukemia. N Engl J Med 2011; 364:1027–1036. 62. Burnett AK, Russell NH, Hills RK, et al. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol 2013; 31:3360– 3368. 63. Gandhi V, Estey E, Keating MJ, Plunkett W. Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy. J Clin Oncol 1993; 11:116–124. 64. Borthakur G, Cortes JE, Estey EE, et al. Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAGGO) as front-line regimen in patients with core binding factor acute myelogenous leukemia. Am J Hematol 2014; 89:964–968. 65. Borthakur G, Kantarjian H, Wang X, et al. Treatment of core-binding-factor in acute myelogenous leukemia with fludarabine, cytarabine, and granulocyte colony-stimulating factor results in improved event-free survival. Cancer 2008; 113:3181–3185. 66. Marcucci G, Geyer S, Zhao W, et al. Adding KIT inhibitor dasatinib (DAS) to chemotherapy overcomes the negative impact of KIT mutation/over-expression in core binding factor (CBF) acute myeloid leukemia (AML): results from CALGB 10801 (Alliance) [abstract]. American Society of Hematology annual meeting and exposition. San Francisco 2014. 67. Boissel N, Jourdan E, Pigneux A, et al. Single-agent dasatinib does not prevent hematological relapse in patients with core binding factor (CBF) acute myeloid leukemia (AML) in first complete remission, but persistent or re-appearing molecular minimal residual disease-results of the DASACBF trial from the French AML intergroup [abstract]. Blood 2011; 118: 2608. 68. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol 2014; 15:986–996. 69. Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002; 100:4372–4380. 70. Bornhauser M, Illmer T, Schaich M, et al. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood 2007; 109:2264–2265. [Author reply 2265] 71. DeZern AE, Sung A, Kim S, et al. Role of allogeneic transplantation for FLT3/ ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transplant 2011; 17:1404–1409. 72. Laboure G, Dulucq S, Labopin M, et al. Potent graft-versus-leukemia effect after reduced-intensity allogeneic SCT for intermediate-risk AML with FLT3ITD or wild-type NPM1 and CEBPA without FLT3-ITD. Biol Blood Marrow Transplant 2012; 18:1845–1850. 73. Lin PH, Lin CC, Yang HI, et al. Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3. Leuk Res 2013; 37:287– 292. 74. Rollig C, Bornhauser M, Thiede C, et al. Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system. J Clin Oncol 2011; 29:2758–2765. 75. Brunet S, Labopin M, Esteve J, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol 2012; 30:735–741. 76. Gale RE, Hills R, Kottaridis PD, et al. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood 2005; 106:3658– 3665.
77. Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 2008; 111:2776–2784. 78. Pratcorona M, Brunet S, Nomdedeu J, et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to postremission therapy. Blood 2013; 121:2734–2738. 79. Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and & insertion site in FLT3-ITD positive AML with respect to allogeneic hematopoietic stem cell transplantation. Blood 2014; 124:3441–3449. This study illustrated the potential utility of FLT3 mutant level on PRT choice. 80. Burnett AK, Goldstone A, Hills RK, et al. Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission. J Clin Oncol 2013; 31:1293–1301. 81. Walter RB, Pagel JM, Gooley TA, et al. Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission. Leukemia 2010; 24:1276–1282. 82. Garcia JS, Medeiros BC, Appelbaum FR. Blood consult: monosomal karyotype acute myeloid leukemia. Blood 2012; 119:5659–5660. 83. Medeiros BC, Othus M, Fang M, et al. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience. Blood 2010; 116:2224–2228. 84. Ahn HK, Jang JH, Kim K, et al. Monosomal karyotype in acute myeloid leukemia predicts adverse treatment outcome and associates with high functional multidrug resistance activity. Am J Hematol 2012; 87:37–41. 85. Bejar R, Stevenson KE, Caughey B, et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stemcell transplantation. J Clin Oncol 2014; 32:2691–2698. 86. Yanada M, Kurosawa S, Yamaguchi T, et al. Prognosis of acute myeloid leukemia harboring monosomal karyotype in patients treated with or without allogeneic hematopoietic cell transplantation after achieving complete remission. Haematologica 2012; 97:915–918. 87. Fang M, Storer B, Estey E, et al. Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation. Blood 2011; 118:1490–1494. 88. Cornelissen JJ, Breems D, van Putten WL, et al. Comparative analysis of the value of allogeneic hematopoietic stem-cell transplantation in acute myeloid leukemia with monosomal karyotype versus other cytogenetic risk categories. J Clin Oncol 2012; 30:2140–2146. 89. Basara N, Schulze A, Wedding U, et al. Early related or unrelated haematopoietic cell transplantation results in higher overall survival and leukaemia-free survival compared with conventional chemotherapy in high-risk acute myeloid leukaemia patients in first complete remission. Leukemia 2009; 23:635–640. 90. Schlenk RF, Dohner K, Mack S, et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German–Austrian trial AMLHD98A. J Clin Oncol 2010; 28:4642–4648. 91. Atsuta Y, Suzuki R, Nagamura-Inoue T, et al. Disease-specific analyses of unrelated cord blood transplantation compared with unrelated bone marrow transplantation in adult patients with acute leukemia. Blood 2009; 113:1631– 1638. 92. Huang XJ, Zhu HH, Chang YJ, et al. The superiority of haploidentical related stem cell transplantation over chemotherapy alone as postremission treatment for patients with intermediate- or high-risk acute myeloid leukemia in first complete remission. Blood 2012; 119:5584–5590. 93. 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; 351:2276–2285. 94. 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; 9:579–590.
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Is it time to change conventional consolidation chemotherapy for acute myeloid leukemia in CR1? Ofir Wolach and Richard M. Stone
Purpose of review Choosing the most appropriate postremission therapy (PRT) for a patient with acute myeloid leukemia (AML) in first complete remission remains a challenging task. Factors such as risk for disease relapse, nonrelapse mortality associated with different PRT approaches, donor availability, prospects for salvage should disease relapse, and patient preference all affect PRT choice. Recent findings New genetic markers refine AML risk stratification and identify patients within the ‘classical’ risk groups who may benefit from transplant-based or chemotherapy-based PRT. The use of minimal residual disease in first remission to guide PRT choice and the application of novel, targeted therapies have the potential to alter PRT approaches across AML risk groups. The advent of alternative donor sources, use of reduced intensity regimens, and improved supportive care all affect the availability and safety of transplant-based PRT and challenge the relevance of the older legacy ‘donor/no-donor’ genetically randomized trials. Summary Genetic risk assessment, monitoring of minimal residual disease in first remission, use of targeted agents, and the newer transplant strategies all have the potential to ‘personalize’ PRT choice in the AML patient. The clinical value of these novel interventions awaits validation in prospective, risk-adapted clinical trials. Keywords acute myeloid leukemia, allogeneic stem cell transplant, first remission, postremission therapy
INTRODUCTION The principles that guide the therapeutic approach to younger patients with acute myeloid leukemia (AML) have changed little over the years: high-dose chemotherapy to induce remission and restore normal hematopoiesis followed by postremission therapy (PRT) directed at elimination of disease [1]. Four decades since ‘3 þ 7’ induction therapy with daunorubicin and cytarabine was first introduced [2], it is still regarded (with minor alterations) as a standard induction regimen. How to manage the patient once first complete remission is attained is a matter of ongoing controversy that can be essentially summarized by the question: Who should get a transplant in first remission? A clear answer to this question is not easy to give for several reasons: (1) AML encompasses a heterogeneous group of diseases that differ in molecular pathophysiology [3]. The prognostic significance of specific mutations as well as the effect of mutational patterns are an ongoing focus of research [4]. To
date, internal tandem duplications in the fms-like tyrosine kinase 3 gene (FLT3-ITD) and mutations in nucleophosmin1 (NPM1) and in CCAAT/enhancer-binding protein alpha (CEBPA) are the ones most likely to affect PRT [5,6]. Targeted interventions against recently discovered (driver) mutations may affect PRT choice in the future. (2) Predicting relapse risk in the specific patient remains a challenge. The advent of techniques that assess minimal residual disease (MRD) in first remission are promising and were shown to have prognostic value [7,8], but still need to be
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Correspondence to Richard M. Stone, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA. Tel: +1 617 632 2214; fax: +1 617 632 2933; e-mail: [email protected] Curr Opin Hematol 2015, 22:123–131 DOI:10.1097/MOH.0000000000000119
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Myeloid disease
KEY POINTS The choice of the most appropriate postremission approach for the AML patient in first remission is complex and should take into account several factors including disease-related factors (relapse risk), patientrelated factors (performance status, patient preference), and transplant-related factors (donor availability, predicted NRM). The abundance of new genetic prognostic markers may identify patients within the ‘classic’ cytogenetic risk group for which different postremission approaches may be advisable. Monitoring minimal residual disease in first remission holds promise as a tool to direct postremission therapy. The advent of novel, targeted approaches may affect choice of postremission intervention (e.g. dasatinib in core binding factor leukemia). The clinical value of these novel interventions awaits validation in prospective, risk-adapted clinical trials.
validated in the context of prospective PRT decision analysis. (3) Most prospective comparisons of allogeneic stem cell transplant (alloSCT) and chemotherapy in first remission via sibling donor-based allocation were done in an era when matched related sibling donors and myeloablative conditioning were applied. Better supportive care, the use of matched unrelated donors (MUDs) as well as alternative donor sources and reduced intensity preparative regimens all challenge the relevance of the older data sets [9–14]. Robust, evidence-based data concerning the effect of these changes on PRT choice are needed.
RISK-ADAPTED APPROACH TO POSTREMISSION THERAPY: A MOVING TARGET Diagnostic cytogenetics is of cardinal importance in predicting remission, risk of relapse, and survival in patients treated for AML [15–17]. Patients currently are stratified into three prognostic groups based on cytogenetics. Those harboring core binding factor (CBF) translocations [inv16, t(8;21)] have a predicted long-term survival of approximately 65%. Patients with poor outcome include patients with deletions of the long arms of chromosome 5 or 7, complex karyotypes (3 chromosomal abnormalities), and translocations involving the EVI1 gene at 3q26. Within this adverse group, patients with monosomal karyotype do extremely poorly with long-term survival well under 10% [18,19]. The poor outcome of patients with monosomal karyotype probably stems from its association with p53 loss of function predicting chemo-resistant disease [20]. The intermediate-risk group mainly consists of patients with normal cytogenetics (40–50% of all AML patients) who have an approximate 40% likelihood for long-term survival. In this group, the presence of mutations in NPM1 with negative FLT3-ITD status or bi-allelic mutated CEBPA confers outcomes comparable to those of patients with CBFAML [21] (Table 1). Every large cooperative trial (mostly done in the last millennium) that assessed the value of alloSCT in first remission failed to demonstrate an overall survival (OS) advantage for alloSCT, mainly because the clear advantage in terms of reducing relapse rates was offset by the much higher treatment-related mortality [22–29]. These trials employed ‘genetic randomization’, meaning that patients with a matched related sibling were allocated to alloSCT,
Table 1. Estimated outcomes of patients with acute myeloid leukemia based on integrated genetic and cytogenetic risk Risk group
Cytogenetics/genetics
Approximate 4-year OS
Approximate prevalence
Very high
Monosomal karyotypea
10%
6%
High
Complex karyotype
20%
12%
35%
25%
Other unfavorable cytogenetics Intermediate
Normal cytogenetics (nonfavorable genetic pattern) Other nonfavorable and nonadverse cytogenetics
Favorable Very favorable
Inv16 or t(8;21) with c-KITmut
40%
5%
Normal cytogenetics with FLT3-ITDneg/NPM1pos
50%
25%
Normal cytogenetics with double CEBPA mutations
60%
5%
Inv16 or t(8;21) with c-KITWT
65%
10%
t(15;17)
85%
12%
CEBPA, CCAAT/enhancer-binding protein alpha; FLT3-ITD, fms-like tyrosine kinase 3 gene; NPM1, nucleophosmin1; OS, overall survival. Previously published. Source [1]. a Usually associated with P53 alterations.
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Postremission therapy for myeloid leukemia Wolach and Stone
whereas others received a non-alloSCT PRT [with a second randomization to intensive chemo vs. autologous transplant (autoSCT) in some cases]. Subgroup analysis depicted a consistent survival benefit for alloSCT in the adverse-risk group; no clear conclusion as to the best PRT in intermediate and favorable groups could be drawn. For example, in the EORTC/GIMEMA AML10 trial, alloSCT was found to significantly improve survival in the adverse-risk group (4-year OS of 50 vs. 29%; more so in younger patients), but not in the favorable or intermediate groups [28]. However, the MRC trial suggested benefit of alloSCT only in intermediate-risk patients [30]. Slovak et al. analyzed the effect of cytogenetics on outcome in 412 younger newly diagnosed patients with AML in first remission enrolled onto a SWOG/ECOG trial; multivariate analysis showed that alloSCT was better than chemotherapy or autoSCT in patients with adverse cytogenetics. Intermediate-risk patients seemed to benefit more from chemotherapy. In this analysis, and in contrast to most other studies, favorable-risk patients fared better with autoSCT or alloSCT as compared to chemotherapy alone [17]. Several meta-analyses attempted to more clearly guide risk-adapted PRT choice [24,31,32]. In the largest of these studies, Koreth et al. [31] analyzed 24 trials (including 6007 patients) and demonstrated a significant OS advantage for alloSCT in first remission for patients with intermediate and high risk, but not for those with favorable-risk AML. Matched pairs analysis of patients enrolled onto the German AMLCG99 trial was recently reported [33 ]. Matching was done prospectively and patients were matched in similar time frames within the study, thus controlling for trends in supportive care and practice that could influence outcome. One hundred and eighty-five matched pairs of newly diagnosed AML patients younger than 60 years were controlled for age, AML type, cytogenetic risk and time in complete remission. Patients were not prospectively matched for FLT3 and NPM1 status, although these genetic mutations were equally prevalent in both groups. Patients with intermediate risk and a matched-sibling donor and those with high-risk disease with a matched-sibling donor or MUD were offered transplant in first remission. OS at 7 years was significantly better for patients in the alloSCT arm (58 vs. 46%) as was relapse-free survival (RFS; 52 vs. 33%). Subgroup analysis suggested that the benefit of alloSCT was more pronounced in patients with adverse risk, those with intermediate risk and abnormal cytogenetics, and in early responders (based on day 15 marrow). In contrast to prior studies [28,30], patients 45–59 years had most benefit from alloSCT, possibly reflecting better &
supportive care and age-appropriate conditioning regimens.
IS HIGH-DOSE CYTARABINE THE RIGHT CHOICE FOR ALL CYTOGENETICALLY FAVORABLE PATIENTS: THE CASE OF CORE BINDING FACTOR LEUKEMIA The pivotal CALGB 8525 trial demonstrated the superiority of repetitive cycles of high-dose cytarabine (HiDAC) for consolidation therapy compared with lower doses [34]. Subgroup analysis demonstrated that most of the benefit from HiDAC was observed in patients with CBF-AML (complete remission rate of 78% and 5-year OS of 64%) [35]. Additional analyses underscored the importance of 3–4 cycles of HiDAC consolidation (as opposed to fewer cycles) in attaining maximal benefit from cytarabine [36,37], and suggested that RAS-mutated patients might be in the likely-to-benefit group [38]. One-third to one-half of patients with so-called ‘favorable-risk’ leukemia experience disease relapse with a HiDAC-based PRT approach, but are there patients with CBF-AML who may benefit from a transplant-based approach? Risk factors for treatment failure in CBF leukemia include older age [39–41], higher white blood cell count at diagnosis [39,42,43], therapy-related disease [44,45], lower platelet counts [40,43], non-white ethnicity [40], and loss of Y chromosome [43] (the latter two only for 8;21). Deletion of the long arm of chromosome 9 and trisomy 22 were associated with favorable outcome in patients with (8;21) and inv16, respectively [40,43]. However, adverse risk cannot be assumed to be an indication for alloSCT without prospective data. In one retrospective study, the outcome of 132 patients with CBF-AML treated with chemotherapy within German cooperative trials was compared with that of 118 patients with CBF-AML who had alloSCT and whose information was extracted from the CIBMTR registry. Patients with loss of sex chromosome had similar outcome, regardless of PRT employed, whereas patients without such a chromosome loss fared less with alloSCT [46]. Activating mutations in KIT are found in approximately one-third of patients with CBF-AML and may occur in exon 17 (encoding the activation loop of the receptor) or exon 8 (in the extracellular domain). KIT mutations are generally regarded as indicators of poor prognosis, although data are not consistent across studies and are more robust for (8;21) [47]. According to the latest National Comprehensive Cancer Network guidelines, the presence of KIT mutation in CBF will render a patient intermediate risk [6] such that more aggressive PRT or clinical trial should be considered. Since KIT mutations
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seem to drive proliferation and affect outcome, and KIT is highly expressed even in nonmutated CBF-AML patients [47], inhibition of KIT may be an attractive therapeutic target. Additional genetic lesions (FLT3-ITD, FLT3-TKD, NRAS, KRAS, and CBL), specific gene expression profiles, and overexpression of BAALC and MN1 [39,48–51] may affect outcome, but their effect on PRT choice is yet to be defined. In pediatric acute lymphoblastic leukemia, the presence of MRD after induction is a poor prognostic sign and often considered an indication for alloSCT. What is the situation in CBF-AML? Jourdan et al. [52] recently reported on 198 CBF-AML patients (ages 18–60) who were randomly assigned to standard vs. intensive induction followed by three cycles of HiDAC in a multicenter French trial. MRD was serially, prospectively, and centrally measured by quantitative PCR; less than 3-log MRD reduction at the end of first consolidation emerged as the sole predictor of relapse in multivariate analysis. MRD and MRDþ corresponded to a cumulative incidence of relapse and RFS at 36 months of 22 vs. 54% and 73 vs. 44%, respectively. Of 278 patients with CBF-AML enrolled in the MRC AML-15 trial, MRD at different time points after induction therapy and during follow-up was predictive of relapse [53]. In a trial including 137 patients with CBF (8;21), AML treated with standard induction followed by two cycles of intermediate-dose cytarabine, PCR-based MRD after second consolidation (less vs. more than 3-log reduction) was used to allocate patients to chemotherapy/autoSCT PRT or alloSCT (matched sibling, MUD, or haploidentical). This risk-adapted approach (actually employed in 69 of 116 patients) was associated with cumulative incidence of relapse of 15% at 5 years (22% in highrisk patients receiving alloSCT and 5% in low-risk patients receiving chemo/autoSCT), disease-free survival of 74.7% at 5 years (61.7% in high-risk and 94.7% in low-risk patients), and OS of 82.7% at 5 years (71.6% in high-risk and 100% in low-risk patients). Of note, KIT mutations were more frequent in the high-risk MRD group (55 vs. 17.6%) and alloSCT showed only a trend towards reducing relapse in this subgroup (although numbers were small) [54 ]. The same group later demonstrated that MRD rather than KIT status can predict post-transplant relapse and can be used to direct preemptive interventions such as donor lymphocyte infusions [55]. Is the long-used HiDAC the optimal chemo for PRT of CBF-AML? This therapy can be associated with significant morbidity and mortality; in the original study by Mayer et al. [34] (in which onethird of patients were over 60 years), 71% of patients required hospitalization after therapy, 12% suffered &
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severe CNS toxicities, and 5% died in complete remission. From a pharmacokinetic standpoint, intracellular saturation of cytarabine’s cytotoxic metabolite, ara-CTP, occurs at drug blood levels that are much lower than those achieved by HiDAC [56,57]. Further escalating the PRT HiDAC dose (beyond the standard Mayer 18 g/m2) did not result in improved efficacy [58]. Moreover, clinical trials that randomized patients to higher dose vs. intermediate doses of cytarabine (in the range of 1–2 g/m2) for PRT showed comparable results, suggesting that HiDAC at 3 g/m2 may be too high [59–62]. The addition of fludarabine was previously suggested to sensitize cells to the cytotoxic effects of cytarabine by inducing the enzyme deoxycytidine kinase [63]; some encouraging results were observed when fludarabine was added to induction and PRT cycles, although this approach has not yet been compared to standard HiDAC [64,65]. Interestingly, in the MRC-AML 15 trial, patients with favourablerisk AML did exceptionally well when FLAG-based induction (fludarabine, cytarabine, and G-CSF) was followed by cytarabine-based consolidation (8-year OS 95%) [62]. The addition of novel and effective agents to therapy of patients with CBF-AML could further change the PRT equation, perhaps improving the prognosis in difficult subsets, thereby making it less likely that any patient will need transplant-based PRT. Among these interventions, adding a tyrosine kinase inhibitor or gemtuzumab ozogamycin (Myelotarg) has the most current potential. A phase II trial (CALGB 10801) assessed the safety and efficacy of adding the KIT inhibitor dasatinib (100 mg/day) to chemotherapy, followed by dasatinib maintenance in patients with CBF-AML (n ¼ 61, age 19–85 years). Younger patients (n ¼ 45) experienced a 93% complete remission rate, and disease-free survival and OS at 2 years were 74 and 96%, respectively. The KIT mutation status did not seem to affect outcome [66]. Another trial found that dasatinib did not prevent overt relapse or progression when given preemptively to patients with CBF-AML and positive MRD [67]. An ongoing phase III trial conducted by the German AMLSG may help to determine if including dasatinib in the therapy of CBF-AML improves outcome. Several phase III RCTs of chemotherapy gemtuzumab ozogamycin in unselected AML yielded inconclusive efficacy results possibly related to different dosing schedules of gemtuzumab ozogamycin and variability in the patients studied, but subgroup analyses suggested that the CBF-AML group had very good outcomes if gemtuzumab ozogamycin was received. A recent meta-analysis consolidated data from five trials and 3325 patients. Volume 22 Number 2 March 2015
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Postremission therapy for myeloid leukemia Wolach and Stone
Although no differences in complete remission rates were noted, a significant OS advantage and a reduction in relapse rates were noted in gemtuzumab ozogamycin arms. Patients with favorable risk benefited most from gemtuzumab ozogamycin, followed by patients with intermediate-risk disease [68]. In summary, ‘one size’ PRT does not fit all in CBF-AML which is more heterogeneous than previously appreciated. We recommend that all CBFAML patients should be screened for KIT mutation. Patients without KIT mutation should get standard HiDAC PRT. All, but particularly those patients whose leukemias harbor mutations, should be considered for clinical trial in which agents such as dasatinib or gemtuzumab ozogamycin are included. Despite the nonavailability of real data, KITmutated CBF-AML patients would at least be strongly considered for transplant-based PRT. Although using the presence of postinduction MRD as an indication for transplant-based PRT
seems promising, we await well-designed, riskadapted trials to test this approach. MRD assessment may also serve as a tool to assess response to new agents and thus guide the choice of PRT (Fig. 1).
PATIENTS WITH INTERMEDIATE-RISK ACUTE MYELOID LEUKEMIA IN FIRST REMISSION: ONGOING CONTROVERSY The approach to PRT in patients with intermediaterisk AML is still a matter of ongoing controversy. Subgroup analysis from the large ‘genetically randomized’ studies yielded conflicting results. The MRC AML 10 analysis reported an OS benefit with alloSCT in these patients [30], the SWOG/ ECOG study suggested chemotherapy performs best in terms of survival [17], and the EORTC/GIMEMA AML 10 and HOVON/SAKK analyses both showed no difference in OS between the different PRT approaches [24,28]; however, the chemotherapybased PRT strategies were nonuniform and
AML in first remissiona
Favorable risk cytogenetics neg
Normal karyotype with FLT3-ITD or double allelic CEBPA
pos
Adverse risk cytogenetics
Normal karyotype with non-favorable genetics
/NPM1
Intermediate risk cytogenetics
High risk features?b No
3-4 cycles of HiDAC
Monosomal karyotype/p53 alteration? No
Yes
Consider AlloSCT within clinical trial
AlloSCT from matched-related or MUD
Yes
alloSCTc
Clinical trial
Clinical trial
AlloSCTc
Targeted therapy (dasatinib, GO) within clinical trial FLT3-ITD allele burden to guide PRT? MRD directed therapy?
Integrated genetic profiling to guide PRT?
AlloSCT from alternative donor sources?
Novel targeted approaches (FLT3 inhibitors)? a
Excluding patients with acute promyelocytic leukemia.
b
For core binding factor leukemia: c-KIT mutation. Additional risk factors that may affect PRT allocation include: WBC
count>20X109/L at presentation, older age at presentation (>35-50 years), therapy related CBF-AML and various secondary genetic alterations (see text). c
Alternative donor sources should be considered if predicted relapse risk very high (>80%) and expected NRM reasonable (0.5) may be those that benefit most from a transplant-based approach [78,79 ]. The role of FLT3 inhibitors in FLT3-positive leukemias and the impact of adding such targeted therapy on PRT choice are actively being investigated. The choice of initial PRT therapy in AML must also consider the effect of salvage after relapse postCR1 chemo vs. alloSCT. An analysis of three MRC trials in younger AML patients (16–49 years) revealed that 5-year survival for patients that relapsed after transplant or no-transplant in CR1 was 7 and 19%, respectively. Among the 1271 patients who relapsed after not being transplanted in CR1, 55% achieved a second remission (82, 54, and 27% in the favorable, intermediate, and adverse groups, respectively), corresponding to a 5-year survival of 32, 17, and 7%, in the favorable, intermediate, and adverse groups, respectively. Patients who were transplanted in second remission had better outcomes than those treated with more &
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chemotherapy (42 vs. 16% at 5 years). An analysis based at least in part on resource utilization suggested that transplant should be deferred until second remission in intermediate-risk patients since this approach would result in similar survival to transplanting all patients [80]. On the basis of the available data, we refer most patients with intermediate-risk disease to alloSCT if a matched donor (related or unrelated [6,12,81]) exists and if patient’s predicted nonrelapse mortality (NRM) is reasonable. Patients who have normal cytogenetics and a ‘favorable’ genetic pattern (FLT3-ITDneg/NPM1pos or those with double allelic CEBPA mutations) receive HiDAC-based PRT [21]. Integrating novel genetic risk factors and MRD into decision analysis awaits further prospective assessment (Fig. 1).
ADVERSE-RISK ACUTE MYELOID LEUKEMIA: DEFINING THE WORST OF THE WORST Patients with adverse cytogenetics have relatively low remission rates and short-lived responses. Virtually all donor/no-donor trials suggest alloSCT in first remission; results are clearly better than for chemo-based PRT, but far from optimal (Table 1) [17,24,28,31,32,33 ]. Within this difficult-to-treat group of patients, those with a monosomal karyotype, defined by the presence of a least two autosomal monosomies or a single autosomal monosomy (excluding loss of sex chromosome) in combination with at least one structural abnormality, constitute the most inferior subgroup. Monosomal karyotype occurs in 10–15% of patients with AML and is more frequent in older age and in the context of secondary leukemia [82]. Analysis of consecutive HOVON/SAKK trials demonstrated a 4-year OS of only 4% (n ¼ 184) as compared to 26% (n ¼ 525) in patients with nonmonosomal karyotype adverse abnormalities [18]. The resistant nature of monosomal karyotype-AML was confirmed in analysis of SWOG (4-year OS of 3%; age 16–88 years) and German (4-year OS of 9%; age 16–85 years) data sets [19,83]. P53 alterations are common in patients with monosomal karyotype (80% in one study [20]). These alterations may account for the poor outcome based on chemoresistance that is perhaps associated with an increase in multidrug resistance pump activity [84]. Moreover, adverse outcome after alloSCT in myelodysplastic syndrome stems from the presence of p53 mutations rather than from the associated complex karyotype [85]; such patients should be considered for clinical trials with novel, targeted therapies (Fig. 1). &
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Postremission therapy for myeloid leukemia Wolach and Stone
Whether alloSCT benefits poor-risk patients is not clear. Monosomal karyotype predicts inferior outcome after alloSCT as compared to other adverse-risk patients [86], and may be so poor as to not yield benefit even in young patients [19]. However, a retrospective analysis from Seattle demonstrated a 4-year OS of 30% among 35 (pediatric and older) patients with monosomal karyotype in first remission; no survivors were noted in the nontransplant control group [87]. A comparative analysis from HOVON/SAKK reported on 107 patients (age 15–60 years) with monosomal karyotype in first remission; alloSCT was performed in 45 patients, chemotherapy in 48 patients, and autoSCT in 14. A survival benefit was noted for patients who were consolidated with alloSCT (matched related or MUD) vs. all other patients with 5-year OS and RFS of 19 vs. 9% (P ¼ 0.02) and 17 vs. 7% (P ¼ 0.003), respectively [88]. In patients with adverse prognosis, a more liberal approach to donor source is frequently exercised because of the grave outcome that is associated with a nontransplant approach. Several retrospective analyses demonstrated comparable outcomes for patients after matched-related or MUD alloSCT [9,12,13,81,89,90]. Alternative donors (partially mismatched unrelated donors, umbilical cord blood, or haploidentical donors) are increasingly utilized in the setting of high-risk disease in which treatment failure with non-alloSCT PRT is felt to overshadow the higher complication rate and NRM associated with these donor sources. Several uncontrolled studies suggest that alternative donor sources may be beneficial in the high-risk setting [14,91– 93]. In a recent consensus statement from the European LeukemiaNet, alloSCT from an alternative donor was endorsed in patients with more than 80% relapse risk who lack a matched-related or MUD and who have an anticipated nonrelapse mortality of less than 35% [94].
CONCLUSION Choosing the most appropriate PRT approach for a patient in first complete remission remains a challenging task. The main factors that should affect decision analysis include the risk for disease relapse (based on clinical presentation, cytogenetics, and mutations), the competing risk of NRM, donor availability, the prospects for successful salvage should patient relapse and of course patient preference. The abundance of prognostic information that stems from molecular studies adds another level of complexity in correctly predicting the risk of relapse. The rate at which new prognostic information is introduced to the clinic is extraordinary,
but the precise role of most of these data awaits validation in prospective, risk-adapted clinical trials. The same applies for the application of MRD monitoring in first remission. The advent of novel, targeted therapies is another consequence of the growing understanding of the pathways (genetic and others) that drive leukemia. These agents may also impact the decision on PRT. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest R.M.S. – BMS, ad hoc consultant; O.W. – none.
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Prognosis of inv(16)/t(16;16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup. Blood 2003; 102:462–469. 42. Nguyen S, Leblanc T, Fenaux P, et al. A white blood cell index as the main prognostic factor in t(8;21) acute myeloid leukemia (AML): a survey of 161 cases from the French AML Intergroup. Blood 2002; 99:3517–3523. 43. Schlenk RF, Benner A, Krauter J, et al. Individual patient data-based metaanalysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol 2004; 22:3741–3750. 44. Borthakur G, Lin E, Jain N, et al. Survival is poorer in patients with secondary core-binding factor acute myelogenous leukemia compared with de novo core-binding factor leukemia. Cancer 2009; 115:3217–3221. 45. Gustafson SA, Lin P, Chen SS, et al. 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Volume 22 Number 2 March 2015
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Postremission therapy for myeloid leukemia Wolach and Stone 61. Lowenberg B, Pabst T, Vellenga E, et al. Cytarabine dose for acute myeloid leukemia. N Engl J Med 2011; 364:1027–1036. 62. Burnett AK, Russell NH, Hills RK, et al. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol 2013; 31:3360– 3368. 63. Gandhi V, Estey E, Keating MJ, Plunkett W. Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy. J Clin Oncol 1993; 11:116–124. 64. Borthakur G, Cortes JE, Estey EE, et al. Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAGGO) as front-line regimen in patients with core binding factor acute myelogenous leukemia. Am J Hematol 2014; 89:964–968. 65. Borthakur G, Kantarjian H, Wang X, et al. Treatment of core-binding-factor in acute myelogenous leukemia with fludarabine, cytarabine, and granulocyte colony-stimulating factor results in improved event-free survival. Cancer 2008; 113:3181–3185. 66. Marcucci G, Geyer S, Zhao W, et al. Adding KIT inhibitor dasatinib (DAS) to chemotherapy overcomes the negative impact of KIT mutation/over-expression in core binding factor (CBF) acute myeloid leukemia (AML): results from CALGB 10801 (Alliance) [abstract]. American Society of Hematology annual meeting and exposition. San Francisco 2014. 67. Boissel N, Jourdan E, Pigneux A, et al. Single-agent dasatinib does not prevent hematological relapse in patients with core binding factor (CBF) acute myeloid leukemia (AML) in first complete remission, but persistent or re-appearing molecular minimal residual disease-results of the DASACBF trial from the French AML intergroup [abstract]. Blood 2011; 118: 2608. 68. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol 2014; 15:986–996. 69. Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002; 100:4372–4380. 70. Bornhauser M, Illmer T, Schaich M, et al. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood 2007; 109:2264–2265. [Author reply 2265] 71. DeZern AE, Sung A, Kim S, et al. Role of allogeneic transplantation for FLT3/ ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transplant 2011; 17:1404–1409. 72. Laboure G, Dulucq S, Labopin M, et al. Potent graft-versus-leukemia effect after reduced-intensity allogeneic SCT for intermediate-risk AML with FLT3ITD or wild-type NPM1 and CEBPA without FLT3-ITD. Biol Blood Marrow Transplant 2012; 18:1845–1850. 73. Lin PH, Lin CC, Yang HI, et al. Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3. Leuk Res 2013; 37:287– 292. 74. Rollig C, Bornhauser M, Thiede C, et al. Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system. J Clin Oncol 2011; 29:2758–2765. 75. Brunet S, Labopin M, Esteve J, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol 2012; 30:735–741. 76. Gale RE, Hills R, Kottaridis PD, et al. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood 2005; 106:3658– 3665.
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