- Email: [email protected]
Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?
Best Practice & Research Clinical Haematology xxx (2017) 1e6
Contents lists available at ScienceDirect
Best Practice & Research Clinical Haematology journal homepage: www.elsevier.com/locate/beha
Do cytogenetics affect the post-remission strategy for older patients with AML in CR1? James M. Foran Mayo Clinic Cancer Center, 4500 San Pablo Road, Jacksonville, FL 32224, USA
a b s t r a c t Keywords: Acute myeloid leukemia Age AML Azacitidine Clofarabine Consolidation CPX-351 Cytarabine Cytogenetics Daunorubicin Decitabine Minimal residual disease MRD Reduced intensity conditioning RIC Risk TP53 Transplant
Data have shown that intensified cytarabine in consolidation for treatment of acute myeloid leukemia (AML) does not equally benefit patients older than 60 years, and older patients experience significantly more neurotoxicity than younger patients. In addition, older patients are more likely to have abnormal or unfavorable cytogenetics, which also tend to confer limited efficacy with intensified cytarabine. This poses a treatment dilemma as to the best post remission therapy to treat older patients. This review explores some of the consolidation treatment strategies and options available for the older AML patient. © 2017 Elsevier Ltd. All rights reserved.
1. Introduction When considering the topic of this paper, most physicians will agree that acute myeloid leukemia (AML) biology predicts response and relapse after standard intensive therapy, particularly for younger patients. National Comprehensive Cancer (NCCN) guidelines and updates from European LeukemiaNet (ELN) 2017 identify cytogenetic risk groups and classify them into better (favorable) risk, intermediate risk, or poor (adverse) risk, sometimes incorporating molecular abnormalities into the classifications (Table 1) [1,2]. Older data using Cancer and Leukemia Group B (CALGB) criteria demonstrate that relapse is strongly correlated with a patient's cytogenetic risk [3]. Similarly, even earlier CALGB data showed that intensified cytarabine in consolidation, which is primarily the focus of this paper, improves remission duration in patients with more favorable cytogenetics, such as core binding factor (CBF) leukemia, and to a lesser extent in patients with normal cytogenetics [4]. However, intensified cytarabine consolidation has limited efficacy in patients with abnormal cytogenetics. These data are from a predominantly younger patient population, with only about 10% of the cohort older than 60 years. In yet an earlier study from CALGB, younger patients experienced a benefit from higher doses of cytarabine versus lower-dose infusional cytarabine [5]. Patients older than 60 received no apparent or uniform benefit from cytarabine intensification and
E-mail address: [email protected]. https://doi.org/10.1016/j.beha.2017.09.008 1521-6926/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Foran JM, Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?, Best Practice & Research Clinical Haematology (2017), https://doi.org/10.1016/j.beha.2017.09.008
2
J.M. Foran / Best Practice & Research Clinical Haematology xxx (2017) 1e6
Table 1 AML biology predict response and relapse after cytarabine þ anthracycline chemotherapy.
experienced significantly more neurotoxicity with high-dose cytarabine. Older patients are most likely to have abnormal or unfavorable cytogenetics and the least likely to benefit from intensified cytarabine consolidation, which poses a significant treatment dilemma in remission.
2. Cytogenetics and post remission therapy in older adults AML is at the same time generally a disease of older people. The median age of individuals with newly diagnosed AML ranges from 68 to 72 years. AML incidence increases with age, peaking in the 80- to 84-year-old group. Data from the Swedish Acute Leukemia Registry, which contained 2866 cases of AML diagnosed from January 1997 through September 2005, found the median age to be 72 years (range, 16e97 years) with a mean of 68 years. Males were a median 71 years and females, 72 years [6]. By modeling the frequency of remission induction therapy over these data, it's clear that in patients older than 65, there's a rapidly diminishing number who undergo intensive therapy (Fig. 1). And most patients over 70 years do not receive intensive
Fig. 1. A diminishing number of patients older than 65 years undergo intensive therapy, and most over 70 years do not receive intensive induction therapy. Cytogenetics could potentially be of use in this population to predict relapse or to model the best post remission therapy to administer.
Please cite this article in press as: Foran JM, Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?, Best Practice & Research Clinical Haematology (2017), https://doi.org/10.1016/j.beha.2017.09.008
J.M. Foran / Best Practice & Research Clinical Haematology xxx (2017) 1e6
3
induction therapy. Would cytogenetics be of use in that population to predict relapse or to model the best post remission therapy to administer? Only a minority of patients over 65 years are eligible for and receive true intensive remission induction therapy. The complete remission (CR) rates are much lower in this population, which means fewer than half go on to receive consolidation therapy. Randomized studies have demonstrated that intensive consolidation is poorly tolerated by the older patient and no evidence indicates that intensification of cytarabine dose is helpful for them [7]. Likewise, there is no evidence that the addition of alternative chemotherapy agents, or with very few or limited exceptions [8], that continuation therapy or extended therapy with consolidation is helpful. Because very few older patients with adverse cytogeneticsdabout 10%d actually go on to receive post remission therapy, it is particularly difficult to gain insight into its benefits for this cohort. This significantly limits the power to observe differences in patients over 60 or 65 years with adverse cytogenetics to determine whether some consolidation strategy is better than another, if it all. A sobering observation from a paper by Appelbaum et al. begs the question of whether there is indeed such a phenomenon as an intermediate risk patient over age 65 [9]. The Southwest Oncology Group (SWOG) study evaluated overall survival by age for patients with intermediate risk cytogenetics. Patients younger than 56 years (n ¼ 149) had a median survival of 26 months, patients aged 56e65 years (n ¼ 101) had a median survival of 12 months, patients aged 66e75 years (n ¼ 110) had a median survival of 8 months, and patients older than 75 years (n ¼ 24) had a median survival of 7 months. It is difficult to determine a more effective post remission therapy then in this population as the poor outcomes are most likely due to a combination of factorsdpoor performance status, advanced age, worse cytogenetics, worse disease characteristics, and poorly tolerated therapy, among other factors. Certain subgroups are known to be more favorable in younger patients than in older ones. For example, patients with normal karyotype, isolated NPM1 mutation and wild type FLT3 who are 65 or younger have a significantly better overall survival, in contrast to patients older than 65 in whom it does not appear to be favorable [10]. This supports the argument that intermediate or favorable risk disease in the older patient does not truly exist, even in those with more favorable characteristics. A recent report did observe that multiple courses of intermediate-dose cytarabine could achieve a 39% 5-year survival rate in older adults with AML and isolated NPM1 mutation, suggesting that it might be possible to select a molecular subset who may benefit from intensified consolidation, but this represents a selected patient cohort and remains to be confirmed [11]. Therefore, it has been difficult to identify a better subgroup in this population and to establish a ‘best’ and individualized post remission therapy for this population. 3. Discovering the best post remission therapy 3.1. High-intensity therapy Clofarabine has been investigated as an intermediate intensity drug for induction and consolidation. The E2906 study compared clofarabine at 30 mg/m2 to standard full-intensity daunorobucin at 60 mg/m2 and cytarabine at 100 mg/m2 (7 þ 3) [12]. Patients were HLA typed at baseline and strongly encouraged to proceed to allogeneic stem cell transplant after achieving a complete response to induction therapy on either arm. The study had a second randomization for 12 months maintenance decitabine after consolidation. The primary analysis found no difference in the CR rate between the two arms. However, patients with intermediate risk had significantly better overall survival on standard therapy than on clofarabine (P ¼ 0.001). There was no difference between the arms in unfavorable risk patients (P ¼ 0.78). In this study, older patients received an intermediate dose level of cytarabine and they had the same complete remission rate. This raised the question of whether the difference in survival was the result of the intensive consolidation, particularly in the intermediate risk group that led to the survival difference. We therefore performed a landmark analysis to determine the risk factors for survival from remission after induction therapy [13]. We analyzed the effect of remission status, remission quality, and other factors in subsequent survival beginning at day 60 from trial registration. We did not find a clear impact of cytogenetics in that situation. We found subsequent survival was driven almost solely by patients' achieving CR and the quality of the CR [somewhat contradictory to the finding that the CR rates were the same in both arms]. This begs the question whether minimal residual disease (MRD) was inferior in the clofarabine arm. The landmark analysis also indicated that patients with any response less than a true CR or Cri had a very poor outcome. Again, we were unable to show that cytogenetics in this situation were helpful in discriminating further therapy or further survival. A study of MRD in younger patients with NPM1 mutation receiving intensive therapy found that MRD in complete remission (using an individualized PCR-based platform in a central lab) was the strongest predictor of relapse; abnormal cytogenetics were not predictive [14]. Armed with these results, investigators of E2906 are evaluating whether measuring MRD using flow cytometry can help explain the differences in survival despite the same CR rate. This will help guide post remission therapy strategies in future studies. With low intensity therapies, however, it is difficult to achieve true MRD negativity, or at least a molecular MRD negative state as demonstrated in a recent study of decitabine [15]. CPX-351 is a liposomal formulation containing a fixed combination of cytarabine and daunorubicin, and was compared to standard 7 þ 3 in a recently-reported randomized trial. One of the observations from this trial was that patients who went on to receive an allogeneic transplant had a better survival at the time of transplant. About 50% of the patients had adverse or complex karyotype. One of the inferences, therefore, is that CPX-351 might be a superior consolidation strategy, at least in this Please cite this article in press as: Foran JM, Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?, Best Practice & Research Clinical Haematology (2017), https://doi.org/10.1016/j.beha.2017.09.008
4
J.M. Foran / Best Practice & Research Clinical Haematology xxx (2017) 1e6
analysis where there was a survival advantage after transplant with CPX-351 versus patients who were transplanted following 7 þ 3. This may be one of the very few examples of an improved post remission therapy in patients with higher risk cytogenetics [16]. 3.2. Low-intensity therapy Low-intensity therapy is increasingly being used in patients over 70 years. Most receive low-dose cytarabine or more commonly, hypomethylating agents such as decitabine or azacitidine. It is challenging to determine the best post remission therapy in this population because patients continue on therapy until they fail regardless of whether they achieve CR, and few achieve a true CR or MRD-negative state. Survival after failure is typically very short. Long-term disease-free survival can be achieved after low-intensity induction therapy in select patients with allogeneic transplantation, although this is the exception. Thus, assessing the impact of cytogenetics on alternative strategies after low-intensity therapy is problematic. The MRC AML 14 trial demonstrated an advantage of low-intensity therapy, originally with low-dose cytarabine versus hydroxyurea. There was a small but significant survival advantage in the low-dose cytarabine arm. There was no survival advantage, however, in patients with adverse cytogenetics [17]. Similarly, in a follow-up analysis of the decitabine randomized study versus treatment choice, there was no difference in overall survival with decitabine in patients with adverse cytogenetics [18]. Treatment with azacitidine represents the sole exception [19]: in a report from 2015, patients with adverse cytogenetics had superior overall survival (P ¼ 0.0185) with azacitidine versus conventional care (including low dose cytarabine). This suggests, at least in this group of patients, azacitidine continuation may be a superior induction and maintenance low-intensity treatment strategy. A key issue is how to incorporate targeted mutation studies with cytogenetics to obtain better insight into post-remission therapy. An important example shows a breakdown of mutations in an unselected cohort of AML patients with 3 genetic subtypes: secondary type AML, TP53-mutated AML, and de novo/Pan-AML [20]. The study found a large TP53-mutated population, for which standard therapy is ineffective and outcomes after allogeneic transplant are very poor. A recent study of 116 AML patients indicated in contrast that karyotype and TP53 mutation status didn't affect outcome after decitabine therapy [15]. Most importantly, in this cohort there was a survival advantage for patients who received decitabine and were selected to proceed to allogeneic transplant (P < 0.001). This study provided insight that there may be a better post-remission therapy or consolidation strategy after low-intensity therapy even in high-risk populations, such as patients with TP53 mutations or complex karyotype. The EORTC AML21 study (InDACtion vs 3 þ 7 induction; NCT02172872) is further investigating this concept. Patients are randomized to 2 cycles of induction therapy and 1 or 2 cycles of standard consolidation therapy versus single-agent decitabine for 10 days for first or second induction and then 5 days of decitabine until disease progression or treatment failure. Basically, the study is comparing an abbreviated, intense upfront approach versus a lower-intensity, prolonged approach. Patients have the option to proceed to allogeneic transplant if they are eligible and have adequate disease control. This study will provide important insights as to the role of cytogenetics in determining response, determining survival after lowintensity or high-intensity therapy, and the impact after allogeneic transplant. A paper published in 2015 evaluated the feasibility of reduced-intensity conditioning (RIC) allogeneic transplant in older patients, median age 65 years, in a multicenter CALGB and BMT CTN trial [21]. Patients received RIC of busulfan and fludarabine with antithymocyte globulin (ATG). Rates of acute graft-versus-host disease (GVHD) were low, at 10%, transplantrelated mortality was also low, at 15%, and the 2-year disease-free survival (DFS) and overall survival were 42% and 48%, respectively. Relapse remains an ongoing concern, with a rate of 44%. But in the investigators' analysis, cytogenetics did not significantly influence the risk of relapse. The E2906 study discussed earlier incorporated this same transplant back bone into the treatment regimen, and investigators were strongly encouraged to proceed to transplant for those who had achieved a morphologic leukemia-free state or CR. Donor analysis performed at the time of registration will provide insights as to which group benefitsdthose with a donor or without a donor, those who receive a transplant versus standard therapydderived a survival benefit, and if the therapy is better than standard therapy. 4. New world of clinical trials The Beat AML Master Trial, sponsored by the Leukemia & Lymphoma Society, heralded a new world of clinical trials in 2016. In the first umbrella trial (Fig. 2), patients will be stratified into groups based on their cytogenetic lesions: core binding factor leukemia, MLL rearrangement, or NPM1, IDH1, IDH2, P53 mutations, and so on. Therapy will be based on these stratifications, sometimes with targeted therapies or targeted subgroups, depending on the trial. This will allow investigators to determine in a more focused way the best induction therapy and possibly even consolidation strategy for specific subgroups of patients. 5. Conclusion Cytogenetics remain relevant in disease biology and prognosis even in older patients over the age of 60, despite our inability to show clearly that cytogenetics influence patient outcome after post remission therapy. Insights into the impact of cytogenetic risk on consolidation strategies are also limited, in part because the remission rates are lower and a low CR rate Please cite this article in press as: Foran JM, Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?, Best Practice & Research Clinical Haematology (2017), https://doi.org/10.1016/j.beha.2017.09.008
J.M. Foran / Best Practice & Research Clinical Haematology xxx (2017) 1e6
5
Fig. 2. Schema of the Beat AML Master Trial, in which patients will be stratified into groups based on their cytogenetic lesions and their therapy chosen according to these stratifications.
selects for intermediate-risk patients. Even in the intermediate or sometimes more favorable cytogenetic molecular risk groups, acceptable long-term survival rates are not being achieved. It's very difficult to identify a true intermediate-risk group over the age of 65 that's curable with cytarabine consolidation. It is also difficult to model the impact of post remission treatment in the setting of low-intensity treatment strategies. While still largely anecdotal, many physicians have treated individual patients who are unfit for induction with low intensity decitabine or azacitidine, and who ultimately responded and became fit for and received a curative allogeneic transplant. A forward-looking dataset to work from and identify such candidates does not yet exist, and the EORTC AML21 study might help with that. With some initiatives now underway, physicians can optimize and individualize novel strategies for their patients. One question that arises is whether an adequate response or initial debulking can be adequately defined before moving to some maintenance or consolidation strategy. E2906 may provide some insight if it is re-opened to finish the maintenance decitabine randomization, which is stratified by cytogenetics. The EORTC AML 21 trial will also shed some light on this issue in addition to some very important low-intensity initiatives. Beat AML and the SWOG S1612 initiative, anticipated to open in 2017 or early 2018 will help identify specific therapies and subgroups to improve consolidation strategies. Finally, allogeneic transplants need to be considered more frequently in this population, as it appears to significantly abrogate relapse risk. The ongoing risk of relapse needs to be addressed and novel maintenance or immunotherapy strategies explored. Consulting fees Novartis; Karyopharm; Contracted research: Cellerant; Agios; Boehringer Ingelheim; Seattle Genetics; Takeda. References [1] National Comprehensive Cancer Network. NCCN guidelines: acute myeloid leukemia. June 6, 2017., Version 3.2017. . [Accessed 11 July 2017]. €hner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. [2] Do Blood 2017;129(4):424e47. zek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and [3] Byrd JC, Mro overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100(13): 4325e36. [4] 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;58:4173e9. [5] 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;331:896e903. [6] Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 2009;113(18):4179e87. [7] Stone RM, Berg DT, George SL, et al. Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine. Blood 2001;98(3):548e53. [8] Gardin C, Turlure P, Fagot T, et al. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood 2007;109(12):5129e35.
Please cite this article in press as: Foran JM, Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?, Best Practice & Research Clinical Haematology (2017), https://doi.org/10.1016/j.beha.2017.09.008
6
J.M. Foran / Best Practice & Research Clinical Haematology xxx (2017) 1e6
[9] Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood 2006;107(9):3481e5. [10] Ostronoff F, Othus M, Lazenby M, et al. Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report. J Clin Oncol 2015;33(10):1157e64. €ll I, et al. Karyotype plus NPM1 mutation status defines a group of elderly patients with AML (60 years) who benefit from [11] Sperr WR, Zach O, Po intensive post-induction consolidation therapy. Am J Hematol 2016;91(12):1239e45. [12] Foran JM, Sun Z, Claxton DF, et al. North American Leukemia, Intergroup phase III randomized trial of single agent clofarabine as induction and postremission therapy, and decitabine as maintenance therapy in newly-diagnosed acute myeloid leukemia in older adults (age > 60 years): a rial of the ECOG-ACRIN Cancer Research Group (E2906). Blood 2015;126. abstr 217. [13] Foran JM, Sun Z, Claxton DF, et al. Importance of achieving complete remision (CR) after intensive therapy for acute myeloid leukemia (AML) in older adults age > 60 years: analysis of risk factors for early mortality and re-induction, and impact of quality of response on overall survival (OS) in the ECOG-ACRIN E2906 randomized trial. Blood 2016;128. abstr 339. [14] Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med 2016;374(5):422e33. [15] Welch JS, Petti AA, Miller CA, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med 2016;375(21): 2023e36. [16] Medeiros BC, Hogge D, Newell LF, et al. Overall survival (OS) and stem cell transplant (SCT) in patients with FLT3 mutations treated with CPX-351 versus 7þ3: subgroup analysis of a phase III study of older adults with newly diagnosed, high-risk acute myeloid leukemia (AML). J Clin Oncol 2017:35. [17] Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007;109(6):1114e24. [18] Mayer J, Arthur C, Delaunay J, et al. Multivariate and subgroup analyses of a randomized, multinational, phase 3 trial of decitabine vs treatment choice of supportive care or cytarabine in older patients with newly diagnosed acute myeloid leukemia and poor- or intermediate-risk cytogenetics. BMC Cancer 2014;14:69. [19] Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015;126(3):291e9. [20] Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015;125(9):1367e76. [21] Devine SM, Owzar K, Blum W, et al. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol 2015;33(35):4167e75.
Please cite this article in press as: Foran JM, Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?, Best Practice & Research Clinical Haematology (2017), https://doi.org/10.1016/j.beha.2017.09.008
Contents lists available at ScienceDirect
Best Practice & Research Clinical Haematology journal homepage: www.elsevier.com/locate/beha
Do cytogenetics affect the post-remission strategy for older patients with AML in CR1? James M. Foran Mayo Clinic Cancer Center, 4500 San Pablo Road, Jacksonville, FL 32224, USA
a b s t r a c t Keywords: Acute myeloid leukemia Age AML Azacitidine Clofarabine Consolidation CPX-351 Cytarabine Cytogenetics Daunorubicin Decitabine Minimal residual disease MRD Reduced intensity conditioning RIC Risk TP53 Transplant
Data have shown that intensified cytarabine in consolidation for treatment of acute myeloid leukemia (AML) does not equally benefit patients older than 60 years, and older patients experience significantly more neurotoxicity than younger patients. In addition, older patients are more likely to have abnormal or unfavorable cytogenetics, which also tend to confer limited efficacy with intensified cytarabine. This poses a treatment dilemma as to the best post remission therapy to treat older patients. This review explores some of the consolidation treatment strategies and options available for the older AML patient. © 2017 Elsevier Ltd. All rights reserved.
1. Introduction When considering the topic of this paper, most physicians will agree that acute myeloid leukemia (AML) biology predicts response and relapse after standard intensive therapy, particularly for younger patients. National Comprehensive Cancer (NCCN) guidelines and updates from European LeukemiaNet (ELN) 2017 identify cytogenetic risk groups and classify them into better (favorable) risk, intermediate risk, or poor (adverse) risk, sometimes incorporating molecular abnormalities into the classifications (Table 1) [1,2]. Older data using Cancer and Leukemia Group B (CALGB) criteria demonstrate that relapse is strongly correlated with a patient's cytogenetic risk [3]. Similarly, even earlier CALGB data showed that intensified cytarabine in consolidation, which is primarily the focus of this paper, improves remission duration in patients with more favorable cytogenetics, such as core binding factor (CBF) leukemia, and to a lesser extent in patients with normal cytogenetics [4]. However, intensified cytarabine consolidation has limited efficacy in patients with abnormal cytogenetics. These data are from a predominantly younger patient population, with only about 10% of the cohort older than 60 years. In yet an earlier study from CALGB, younger patients experienced a benefit from higher doses of cytarabine versus lower-dose infusional cytarabine [5]. Patients older than 60 received no apparent or uniform benefit from cytarabine intensification and
E-mail address: [email protected]. https://doi.org/10.1016/j.beha.2017.09.008 1521-6926/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Foran JM, Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?, Best Practice & Research Clinical Haematology (2017), https://doi.org/10.1016/j.beha.2017.09.008
2
J.M. Foran / Best Practice & Research Clinical Haematology xxx (2017) 1e6
Table 1 AML biology predict response and relapse after cytarabine þ anthracycline chemotherapy.
experienced significantly more neurotoxicity with high-dose cytarabine. Older patients are most likely to have abnormal or unfavorable cytogenetics and the least likely to benefit from intensified cytarabine consolidation, which poses a significant treatment dilemma in remission.
2. Cytogenetics and post remission therapy in older adults AML is at the same time generally a disease of older people. The median age of individuals with newly diagnosed AML ranges from 68 to 72 years. AML incidence increases with age, peaking in the 80- to 84-year-old group. Data from the Swedish Acute Leukemia Registry, which contained 2866 cases of AML diagnosed from January 1997 through September 2005, found the median age to be 72 years (range, 16e97 years) with a mean of 68 years. Males were a median 71 years and females, 72 years [6]. By modeling the frequency of remission induction therapy over these data, it's clear that in patients older than 65, there's a rapidly diminishing number who undergo intensive therapy (Fig. 1). And most patients over 70 years do not receive intensive
Fig. 1. A diminishing number of patients older than 65 years undergo intensive therapy, and most over 70 years do not receive intensive induction therapy. Cytogenetics could potentially be of use in this population to predict relapse or to model the best post remission therapy to administer.
Please cite this article in press as: Foran JM, Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?, Best Practice & Research Clinical Haematology (2017), https://doi.org/10.1016/j.beha.2017.09.008
J.M. Foran / Best Practice & Research Clinical Haematology xxx (2017) 1e6
3
induction therapy. Would cytogenetics be of use in that population to predict relapse or to model the best post remission therapy to administer? Only a minority of patients over 65 years are eligible for and receive true intensive remission induction therapy. The complete remission (CR) rates are much lower in this population, which means fewer than half go on to receive consolidation therapy. Randomized studies have demonstrated that intensive consolidation is poorly tolerated by the older patient and no evidence indicates that intensification of cytarabine dose is helpful for them [7]. Likewise, there is no evidence that the addition of alternative chemotherapy agents, or with very few or limited exceptions [8], that continuation therapy or extended therapy with consolidation is helpful. Because very few older patients with adverse cytogeneticsdabout 10%d actually go on to receive post remission therapy, it is particularly difficult to gain insight into its benefits for this cohort. This significantly limits the power to observe differences in patients over 60 or 65 years with adverse cytogenetics to determine whether some consolidation strategy is better than another, if it all. A sobering observation from a paper by Appelbaum et al. begs the question of whether there is indeed such a phenomenon as an intermediate risk patient over age 65 [9]. The Southwest Oncology Group (SWOG) study evaluated overall survival by age for patients with intermediate risk cytogenetics. Patients younger than 56 years (n ¼ 149) had a median survival of 26 months, patients aged 56e65 years (n ¼ 101) had a median survival of 12 months, patients aged 66e75 years (n ¼ 110) had a median survival of 8 months, and patients older than 75 years (n ¼ 24) had a median survival of 7 months. It is difficult to determine a more effective post remission therapy then in this population as the poor outcomes are most likely due to a combination of factorsdpoor performance status, advanced age, worse cytogenetics, worse disease characteristics, and poorly tolerated therapy, among other factors. Certain subgroups are known to be more favorable in younger patients than in older ones. For example, patients with normal karyotype, isolated NPM1 mutation and wild type FLT3 who are 65 or younger have a significantly better overall survival, in contrast to patients older than 65 in whom it does not appear to be favorable [10]. This supports the argument that intermediate or favorable risk disease in the older patient does not truly exist, even in those with more favorable characteristics. A recent report did observe that multiple courses of intermediate-dose cytarabine could achieve a 39% 5-year survival rate in older adults with AML and isolated NPM1 mutation, suggesting that it might be possible to select a molecular subset who may benefit from intensified consolidation, but this represents a selected patient cohort and remains to be confirmed [11]. Therefore, it has been difficult to identify a better subgroup in this population and to establish a ‘best’ and individualized post remission therapy for this population. 3. Discovering the best post remission therapy 3.1. High-intensity therapy Clofarabine has been investigated as an intermediate intensity drug for induction and consolidation. The E2906 study compared clofarabine at 30 mg/m2 to standard full-intensity daunorobucin at 60 mg/m2 and cytarabine at 100 mg/m2 (7 þ 3) [12]. Patients were HLA typed at baseline and strongly encouraged to proceed to allogeneic stem cell transplant after achieving a complete response to induction therapy on either arm. The study had a second randomization for 12 months maintenance decitabine after consolidation. The primary analysis found no difference in the CR rate between the two arms. However, patients with intermediate risk had significantly better overall survival on standard therapy than on clofarabine (P ¼ 0.001). There was no difference between the arms in unfavorable risk patients (P ¼ 0.78). In this study, older patients received an intermediate dose level of cytarabine and they had the same complete remission rate. This raised the question of whether the difference in survival was the result of the intensive consolidation, particularly in the intermediate risk group that led to the survival difference. We therefore performed a landmark analysis to determine the risk factors for survival from remission after induction therapy [13]. We analyzed the effect of remission status, remission quality, and other factors in subsequent survival beginning at day 60 from trial registration. We did not find a clear impact of cytogenetics in that situation. We found subsequent survival was driven almost solely by patients' achieving CR and the quality of the CR [somewhat contradictory to the finding that the CR rates were the same in both arms]. This begs the question whether minimal residual disease (MRD) was inferior in the clofarabine arm. The landmark analysis also indicated that patients with any response less than a true CR or Cri had a very poor outcome. Again, we were unable to show that cytogenetics in this situation were helpful in discriminating further therapy or further survival. A study of MRD in younger patients with NPM1 mutation receiving intensive therapy found that MRD in complete remission (using an individualized PCR-based platform in a central lab) was the strongest predictor of relapse; abnormal cytogenetics were not predictive [14]. Armed with these results, investigators of E2906 are evaluating whether measuring MRD using flow cytometry can help explain the differences in survival despite the same CR rate. This will help guide post remission therapy strategies in future studies. With low intensity therapies, however, it is difficult to achieve true MRD negativity, or at least a molecular MRD negative state as demonstrated in a recent study of decitabine [15]. CPX-351 is a liposomal formulation containing a fixed combination of cytarabine and daunorubicin, and was compared to standard 7 þ 3 in a recently-reported randomized trial. One of the observations from this trial was that patients who went on to receive an allogeneic transplant had a better survival at the time of transplant. About 50% of the patients had adverse or complex karyotype. One of the inferences, therefore, is that CPX-351 might be a superior consolidation strategy, at least in this Please cite this article in press as: Foran JM, Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?, Best Practice & Research Clinical Haematology (2017), https://doi.org/10.1016/j.beha.2017.09.008
4
J.M. Foran / Best Practice & Research Clinical Haematology xxx (2017) 1e6
analysis where there was a survival advantage after transplant with CPX-351 versus patients who were transplanted following 7 þ 3. This may be one of the very few examples of an improved post remission therapy in patients with higher risk cytogenetics [16]. 3.2. Low-intensity therapy Low-intensity therapy is increasingly being used in patients over 70 years. Most receive low-dose cytarabine or more commonly, hypomethylating agents such as decitabine or azacitidine. It is challenging to determine the best post remission therapy in this population because patients continue on therapy until they fail regardless of whether they achieve CR, and few achieve a true CR or MRD-negative state. Survival after failure is typically very short. Long-term disease-free survival can be achieved after low-intensity induction therapy in select patients with allogeneic transplantation, although this is the exception. Thus, assessing the impact of cytogenetics on alternative strategies after low-intensity therapy is problematic. The MRC AML 14 trial demonstrated an advantage of low-intensity therapy, originally with low-dose cytarabine versus hydroxyurea. There was a small but significant survival advantage in the low-dose cytarabine arm. There was no survival advantage, however, in patients with adverse cytogenetics [17]. Similarly, in a follow-up analysis of the decitabine randomized study versus treatment choice, there was no difference in overall survival with decitabine in patients with adverse cytogenetics [18]. Treatment with azacitidine represents the sole exception [19]: in a report from 2015, patients with adverse cytogenetics had superior overall survival (P ¼ 0.0185) with azacitidine versus conventional care (including low dose cytarabine). This suggests, at least in this group of patients, azacitidine continuation may be a superior induction and maintenance low-intensity treatment strategy. A key issue is how to incorporate targeted mutation studies with cytogenetics to obtain better insight into post-remission therapy. An important example shows a breakdown of mutations in an unselected cohort of AML patients with 3 genetic subtypes: secondary type AML, TP53-mutated AML, and de novo/Pan-AML [20]. The study found a large TP53-mutated population, for which standard therapy is ineffective and outcomes after allogeneic transplant are very poor. A recent study of 116 AML patients indicated in contrast that karyotype and TP53 mutation status didn't affect outcome after decitabine therapy [15]. Most importantly, in this cohort there was a survival advantage for patients who received decitabine and were selected to proceed to allogeneic transplant (P < 0.001). This study provided insight that there may be a better post-remission therapy or consolidation strategy after low-intensity therapy even in high-risk populations, such as patients with TP53 mutations or complex karyotype. The EORTC AML21 study (InDACtion vs 3 þ 7 induction; NCT02172872) is further investigating this concept. Patients are randomized to 2 cycles of induction therapy and 1 or 2 cycles of standard consolidation therapy versus single-agent decitabine for 10 days for first or second induction and then 5 days of decitabine until disease progression or treatment failure. Basically, the study is comparing an abbreviated, intense upfront approach versus a lower-intensity, prolonged approach. Patients have the option to proceed to allogeneic transplant if they are eligible and have adequate disease control. This study will provide important insights as to the role of cytogenetics in determining response, determining survival after lowintensity or high-intensity therapy, and the impact after allogeneic transplant. A paper published in 2015 evaluated the feasibility of reduced-intensity conditioning (RIC) allogeneic transplant in older patients, median age 65 years, in a multicenter CALGB and BMT CTN trial [21]. Patients received RIC of busulfan and fludarabine with antithymocyte globulin (ATG). Rates of acute graft-versus-host disease (GVHD) were low, at 10%, transplantrelated mortality was also low, at 15%, and the 2-year disease-free survival (DFS) and overall survival were 42% and 48%, respectively. Relapse remains an ongoing concern, with a rate of 44%. But in the investigators' analysis, cytogenetics did not significantly influence the risk of relapse. The E2906 study discussed earlier incorporated this same transplant back bone into the treatment regimen, and investigators were strongly encouraged to proceed to transplant for those who had achieved a morphologic leukemia-free state or CR. Donor analysis performed at the time of registration will provide insights as to which group benefitsdthose with a donor or without a donor, those who receive a transplant versus standard therapydderived a survival benefit, and if the therapy is better than standard therapy. 4. New world of clinical trials The Beat AML Master Trial, sponsored by the Leukemia & Lymphoma Society, heralded a new world of clinical trials in 2016. In the first umbrella trial (Fig. 2), patients will be stratified into groups based on their cytogenetic lesions: core binding factor leukemia, MLL rearrangement, or NPM1, IDH1, IDH2, P53 mutations, and so on. Therapy will be based on these stratifications, sometimes with targeted therapies or targeted subgroups, depending on the trial. This will allow investigators to determine in a more focused way the best induction therapy and possibly even consolidation strategy for specific subgroups of patients. 5. Conclusion Cytogenetics remain relevant in disease biology and prognosis even in older patients over the age of 60, despite our inability to show clearly that cytogenetics influence patient outcome after post remission therapy. Insights into the impact of cytogenetic risk on consolidation strategies are also limited, in part because the remission rates are lower and a low CR rate Please cite this article in press as: Foran JM, Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?, Best Practice & Research Clinical Haematology (2017), https://doi.org/10.1016/j.beha.2017.09.008
J.M. Foran / Best Practice & Research Clinical Haematology xxx (2017) 1e6
5
Fig. 2. Schema of the Beat AML Master Trial, in which patients will be stratified into groups based on their cytogenetic lesions and their therapy chosen according to these stratifications.
selects for intermediate-risk patients. Even in the intermediate or sometimes more favorable cytogenetic molecular risk groups, acceptable long-term survival rates are not being achieved. It's very difficult to identify a true intermediate-risk group over the age of 65 that's curable with cytarabine consolidation. It is also difficult to model the impact of post remission treatment in the setting of low-intensity treatment strategies. While still largely anecdotal, many physicians have treated individual patients who are unfit for induction with low intensity decitabine or azacitidine, and who ultimately responded and became fit for and received a curative allogeneic transplant. A forward-looking dataset to work from and identify such candidates does not yet exist, and the EORTC AML21 study might help with that. With some initiatives now underway, physicians can optimize and individualize novel strategies for their patients. One question that arises is whether an adequate response or initial debulking can be adequately defined before moving to some maintenance or consolidation strategy. E2906 may provide some insight if it is re-opened to finish the maintenance decitabine randomization, which is stratified by cytogenetics. The EORTC AML 21 trial will also shed some light on this issue in addition to some very important low-intensity initiatives. Beat AML and the SWOG S1612 initiative, anticipated to open in 2017 or early 2018 will help identify specific therapies and subgroups to improve consolidation strategies. Finally, allogeneic transplants need to be considered more frequently in this population, as it appears to significantly abrogate relapse risk. The ongoing risk of relapse needs to be addressed and novel maintenance or immunotherapy strategies explored. Consulting fees Novartis; Karyopharm; Contracted research: Cellerant; Agios; Boehringer Ingelheim; Seattle Genetics; Takeda. References [1] National Comprehensive Cancer Network. NCCN guidelines: acute myeloid leukemia. June 6, 2017., Version 3.2017. . [Accessed 11 July 2017]. €hner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. [2] Do Blood 2017;129(4):424e47. zek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and [3] Byrd JC, Mro overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100(13): 4325e36. [4] 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;58:4173e9. [5] 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;331:896e903. [6] Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 2009;113(18):4179e87. [7] Stone RM, Berg DT, George SL, et al. Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine. Blood 2001;98(3):548e53. [8] Gardin C, Turlure P, Fagot T, et al. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood 2007;109(12):5129e35.
Please cite this article in press as: Foran JM, Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?, Best Practice & Research Clinical Haematology (2017), https://doi.org/10.1016/j.beha.2017.09.008
6
J.M. Foran / Best Practice & Research Clinical Haematology xxx (2017) 1e6
[9] Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood 2006;107(9):3481e5. [10] Ostronoff F, Othus M, Lazenby M, et al. Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report. J Clin Oncol 2015;33(10):1157e64. €ll I, et al. Karyotype plus NPM1 mutation status defines a group of elderly patients with AML (60 years) who benefit from [11] Sperr WR, Zach O, Po intensive post-induction consolidation therapy. Am J Hematol 2016;91(12):1239e45. [12] Foran JM, Sun Z, Claxton DF, et al. North American Leukemia, Intergroup phase III randomized trial of single agent clofarabine as induction and postremission therapy, and decitabine as maintenance therapy in newly-diagnosed acute myeloid leukemia in older adults (age > 60 years): a rial of the ECOG-ACRIN Cancer Research Group (E2906). Blood 2015;126. abstr 217. [13] Foran JM, Sun Z, Claxton DF, et al. Importance of achieving complete remision (CR) after intensive therapy for acute myeloid leukemia (AML) in older adults age > 60 years: analysis of risk factors for early mortality and re-induction, and impact of quality of response on overall survival (OS) in the ECOG-ACRIN E2906 randomized trial. Blood 2016;128. abstr 339. [14] Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med 2016;374(5):422e33. [15] Welch JS, Petti AA, Miller CA, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med 2016;375(21): 2023e36. [16] Medeiros BC, Hogge D, Newell LF, et al. Overall survival (OS) and stem cell transplant (SCT) in patients with FLT3 mutations treated with CPX-351 versus 7þ3: subgroup analysis of a phase III study of older adults with newly diagnosed, high-risk acute myeloid leukemia (AML). J Clin Oncol 2017:35. [17] Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007;109(6):1114e24. [18] Mayer J, Arthur C, Delaunay J, et al. Multivariate and subgroup analyses of a randomized, multinational, phase 3 trial of decitabine vs treatment choice of supportive care or cytarabine in older patients with newly diagnosed acute myeloid leukemia and poor- or intermediate-risk cytogenetics. BMC Cancer 2014;14:69. [19] Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015;126(3):291e9. [20] Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015;125(9):1367e76. [21] Devine SM, Owzar K, Blum W, et al. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol 2015;33(35):4167e75.
Please cite this article in press as: Foran JM, Do cytogenetics affect the post-remission strategy for older patients with AML in CR1?, Best Practice & Research Clinical Haematology (2017), https://doi.org/10.1016/j.beha.2017.09.008