Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia, P Fenaux, GJ Mufti, E Hellström

Tags:
Content: VOLUME 28 NUMBER 4 FEBRUARY 1 2010 JOURNAL OF CLINICAL ONCOLOGY
ORIGINAL REPORT
From the Avicenne, Assistance Publique-Ho^ pitaux de Paris (AP-HP), Universiteґ Paris XIII, Bobigny; Ho^ pital Saint-Louis, AP-HP, Universiteґ Paris 7, Paris, France; King's College Hospital, London, United Kingdom; Karolinska University Hospital (Huddinge), Stockholm, Sweden; Azienda Ospedaliera Universitaria Careggi, Florence, Italy; UniversitaЁ tsklinikum DuЁ sseldorf, DuЁ sseldorf, Germany; Hospital Universitario La Fe, Valencia, Spain; Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Celgene, Summit, NJ; and Mount Sinai School of Medicine, New York, NY. Submitted May 7, 2009; accepted September 28, 2009; published online ahead of print at www.jco.org on December 21, 2009. Supported by research funding from Celgene, Summit, NJ. Presented in part at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2008. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Pierre Fenaux, MD, Service d'Heґ matologie Clinique, Hospital Avicenne, Assistance PubliqueHo^ pitaux de Paris (AP-HP), Universiteґ Paris XIII, 125 route de Stalingrad, 93009 Bobigny, France; e-mail: pierre [email protected] © 2009 by American Society of Clinical Oncology 0732-183X/10/2804-562/$20.00 DOI: 10.1200/JCO.2009.23.8329
Azacitidine Prolongs Overall Survival Compared With Conventional Care Regimens in Elderly Patients With Low Bone Marrow Blast Count Acute Myeloid Leukemia Pierre Fenaux, Ghulam J. Mufti, Eva HellstroЁm-Lindberg, Valeria Santini, Norbert Gattermann, Ulrich Germing, Guillermo Sanz, Alan F. List, Steven Gore, John F. Seymour, Hervґe Dombret, Jay Backstrom, Linda Zimmerman, David McKenzie, C.L. Beach, and Lewis R. Silverman See accompanying editorial on page 521 and articles on pages 549 and 556 ABSTRACT Purpose In a phase III randomized trial, azacitidine significantly prolonged overall survival (OS) compared with conventional care regimens (CCRs) in patients with intermediate-2­ and high-risk myelodysplastic syndromes. Approximately one third of these patients were classified as having acute myeloid leukemia (AML) under current WHO criteria. This analysis compared the effects of azacitidine versus CCR on OS in this subgroup. Patients and Methods Patients were randomly assigned to receive subcutaneous azacitidine 75 mg/m2/d or CCR (best supportive care [BSC] only, low-dose cytarabine (LDAC), or intensive chemotherapy [IC]). Results Of the 113 elderly patients (median age, 70 years) randomly assigned to receive azacitidine (n 55) or CCR (n 58; 47% BSC, 34% LDAC, 19% IC), 86% were considered unfit for IC. At a median follow-up of 20.1 months, median OS for azacitidine-treated patients was 24.5 months compared with 16.0 months for CCR-treated patients (hazard ratio 0.47; 95% CI, 0.28 to 0.79; P .005), and 2-year OS rates were 50% and 16%, respectively (P .001). Two-year OS rates were higher with azacitidine versus CCR in patients considered unfit for IC (P .0003). Azacitidine was associated with fewer total days in hospital (P .0001) than CCR. Conclusion In older adult patients with low marrow blast count (20% to 30%) WHO-defined AML, azacitidine significantly prolongs OS and significantly improves several patient morbidity measures compared with CCR. J Clin Oncol 28:562-569. © 2009 by American Society of Clinical Oncology
INTRODUCTION Acute myeloid leukemia (AML) is associated with poor prognosis in elderly patients,1-3 with 2- and 5-year overall survival (OS) rates of approximately 10% and 2%, respectively.4-6 There are no truly adequate treatments for AML patients.7 Intensive chemotherapy (IC) is often inappropriate as a result of poor performance status, significant comorbidities, adverse tumor cytogenetics, and poor treatment tolerability, leading to treatment-related mortality rates of 10% to 25%.8-12 Treatment with IC is generally limited to 30% to 60% of older AML patients.13 Low-dose cytarabine (LDAC), the farnesyltransferase inhibitor tipifarnib, and gemtuzumab ozogamicin have demonstrated limited impact on survival, whereas the survival impact of new drugs
(eg, clofarabine) remains unproven.14-17 Even IC, when feasible, is associated with a median survival of only 5 to 13 months.11,17-19 Therefore, new treatment options are needed for these patients. In a recent phase III trial, azacitidine (Vidaza; Celgene Corporation, Summit, NJ) demonstrated significantly prolonged OS compared with conventional care regimens (CCRs) in patients with International Prognostic Scoring System­ classified intermediate-2­ and high-risk myelodysplastic syndromes (MDSs).20 This study used the FrenchAmerican-British (FAB) classification for MDS21 and included approximately one third of patients with refractory anemia with excess blasts in transformation (RAEB-t; 20% to 30% bone marrow [BM] blasts). WHO criteria now define AML as 20% BM blasts.22-25 Using those criteria, RAEB-t is now
562 © 2009 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by HODP. UNIVERSITARIO LA FE on May 21, 2010 from . Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.
Azacitidine v Conventional Care Regimens in Low Blast Count AML
A
Enrolled
(N = 113)
Investigator preselection
Best supportive care (n = 63)
Low-dose ara-C (n = 34) Random assignment
Intensive chemotherapy (n = 16)
Azacitidine (n = 36)
Best supportive care (n = 27)
Azacitidine (n = 14)
Low-dose ara-C (n = 20)
Azacitidine (n = 5)
Intensive chemotherapy (n = 11)
B Random assignment
Randomly assigned to treatment (N = 113)
Treatment assigned (efficacy population)
Azacitidine (n = 55)
Conventional care regimens (n = 58)
Best supportive care (n = 27)
Low-dose ara-C (n = 20)
Intensive chemotherapy (n = 11)
Fig 1. CONSORT diagram showing (A) patient enrollment and investigator preselection of conventional care regimen and (B) subsequent random assignment to treatment and treatment received. (*) Seven patients withdrew from the study before receiving treatment and were not included in the safety population; two of the patients were from the azacitidine group, and five were from the conventional care regimen group (best supportive care, n 2; low-dose cytarabine [ara-C], n 2; and intensive chemotherapy, n 1).
Treatment received* (safety population)
Azacitidine (n = 53)
Conventional care regimens (n = 53)
Best supportive care (n = 25)
Low-dose ara-C (n = 18)
Intensive chemotherapy (n = 10)
considered as AML. This analysis compared the relative efficacy and safety of azacitidine versus CCR in this patient subgroup. PATIENTS AND METHODS Study Design and Patients The primary study was a phase III, international, multicenter, random- ized, controlled, parallel-group trial.20 The present analysis included patients with 20% BM or peripheral blasts based on central BM review (ie, with FAB-defined RAEB-t and WHO-defined AML).21,22-25 Additional eligibility criteria included age 18 years, Eastern Cooperative Oncology Group performance status of 0 to 2, and an estimated life expectancy of 3 months. Patients with therapy-related disease; prior treatment with azacitidine, decitabine, or chemotherapy; or planned allogeneic stem-cell transplantation were excluded. Detailed methodology has been previously reported.20 Briefly, before random assignment, investigators selected one of three CCRs (best supportive care [BSC] only, LDAC, or anthracycline plus cytarabine­
based IC) for patients based on age, Eastern Cooperative Oncology Group performance status, and comorbidities (Fig 1). This was an individually based choice that could take into account institutional, regional, or national guidelines.26,27 Patients were then randomly assigned to receive azacitidine or the preselected CCR. No crossover was permitted, and use of erythropoietin or darbepoetin was not allowed. Azacitidine was administered subcutaneously (75 mg/m2/d) for 7 days of every 28-day cycle, for at least six cycles. BSC included blood product transfusions and antibiotics with granulocyte colony-stimulating factor for neutropenic infection. LDAC was administered subcutaneously (20 mg/m2/d) for 14 days of every 28-day cycle, for at least four cycles. IC consisted of induction with cytarabine (100 to 200 mg/m2/d by continuous infusion) for 7 days plus daunorubicin (45 to 60 mg/m2/d), idarubicin (9 to 12 mg/m2/d), or mitoxantrone (8 to 12 mg/m2/d) for 3 days. Patients with complete remission (CR) or partial remission were administered one or two consolidation courses of the same cytotoxic therapy used for induction at reduced doses, followed by BSC. Treatment with azacitidine or LDAC was delayed as appropriate for blood count recovery. All patients could receive BSC, and all treatment regimens
www.jco.org
© 2009 by American Society of Clinical Oncology 563
Information downloaded from jco.ascopubs.org and provided by HODP. UNIVERSITARIO LA FE on May 21, 2010 from . Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.
Fenaux et al
were administered until study end or patient discontinuation as a result of disease progression, unacceptable toxicity, or BM blasts more than 30% with a 50% increase from the pretreatment blast count. Assessment of Efficacy and Safety The primary study end point was OS compared between the azacitidine and combined CCR Treatment Groups. A supportive analysis to the primary end point compared OS between azacitidine and each of the three individual treatments comprising CCR and was based on investigator preselection. Additional supportive analyses compared OS between azacitidine and combined CCR groups in patients considered unfit for IC (ie, preselected to receive BSC or LDAC) and assessed the potential influence of cytogenetics on OS. In the absence of consensus for cytogenetic classification of AML in elderly patients,10 we reclassified patients as having favorable [inv16, t(8,21)], unfavorable (7/7q­ or complex), or intermediate (all others including normal) karyotypes. However, this did not lead to any changes between cytogenetic groups because no patient had a favorable karyotype. Secondary end points were morphologic CR assessed according to International Working Group AML response criteria,28 transfusion independence (absence of RBC or platelet transfusions during 56 consecutive days), adverse events (assessed using National Cancer Institute Common Toxicity Criteria, version 2.0), rate of fever requiring intravenous antibiotics, and hospitalization rates and duration. Statistical Analysis The first patient's informed consent was received on November 24, 2003; the data cutoff date was July 24, 2007. Efficacy analyses included all randomly assigned patients with WHO-defined AML ( 20% BM blasts). OS was defined as time from random assignment until death from any cause and was
assessed using the Kaplan-Meier method and Cox proportional hazards model stratified on the randomized factors of FAB and International Prognostic Scoring System with model term of treatment.21,29 Patients were observed until death or study closure. Patients alive at study closure were censored at date of last observation. treatment effect consistency across preselection groups was assessed by testing the difference in likelihood ratio between two models (treatment preselection interaction terms and treatment alone). The end point used was OS, and homogeneity refers to the homogeneity of hazards of death (or hazard ratio [HR]; azacitidine v CCR) across preselection groups. Response rates were compared for the azacitidine and CCR groups using Fisher's exact test. Safety analyses were performed in patients who received at least one dose of study drug and had one or more postdose safety assessment. Comparisons of transfusion independence, hospitalization, and antibiotic use were analyzed using two approaches: azacitidine versus CCR including patients preselected for IC and azacitidine versus CCR excluding patients preselected for IC. RESULTS Patient Characteristics The study population included 113 patients randomly assigned in the original phase III study who met WHO-AML criteria.20 Of these, two patients had BM counts of 34% and 69%. All 113 patients were included in this intent-to-treat analysis. The efficacy population included 55 patients randomly assigned to azacitidine and 58 patients randomly assigned to CCR. Of the 58 patients in the CCR group, 27
Table 1. Baseline Patient Demographics and Disease Characteristics by Treatment Group and Investigator Preselection
All Patients (N 113)
Azacitidine (n 55)
CCR (n 58)
BSC Only (n 73)
Azacitidine (n 36)
BSC Only (n 27)
LDAC (n 34)
Azacitidine (n 14)
LDAC (n 20)
Intensive Chemotherapy (n 16)
Azacitidine (n 5)
Intensive Chemotherapy (n 11)
Characteristic Age, years Median Range 45-54 55-64 65-74 75 Male Cytogenetic risk group Intermediate Normal Unfavorable Missing ECOG score 0 1 2 Missing Bone marrow blasts, % Median Range Transfusion dependent red blood cells Platelets
No. %
70
52-80
3
5.5
12 21.8
28 50.9
12 21.8
37 67.3
38 69.1
19 34.5
14 25.5
3
5.5
16 29.1
35 63.6
4
7.3
0
23.0 20.0-34.0
34 61.8 15 27.3
No. %
70
50-83
1
1.7
9 15.5
29 50.0
19 32.8
41 70.7
43 74.1
33 56.9
13 22.4
2
3.4
22 37.9
34 58.6
0
2
3.4
23.1 13.0-68.9
39 67.2 10 17.2
No. %
70
52-80
2
5.6
7 19.4
17 47.2
10 27.8
21 58.3
24 66.7
13 36.1
9 25.0
3
8.3
9 25.0 23 63.9 4 11.1 0
22.5 20.0-29.4
22 61.1 9 25.0
No. %
70 56-81 0 3 11.1 14 51.9 10 37.0 16 59.3
19 70.4 12 44.4 8 29.6 0
5 18.5
21 77.8
0
1
3.7
23.0 13.0-29.2
22 81.5 4 14.8
No. %
69
55-78
0
3 21.4
10 71.4
1
7.1
13 92.9
9 64.3 5 35.7 5 35.7 0
5 35.7 9 64.3 0 0
24.2 20.0-34.0
10 71.4 5 35.7
No. %
71 56-83 0 3 15.0 9 45.0 8 40.0 15 75.0
18 90.0
15 75.0
1
5.0
1
5.0
12 60.0
7 35.0
0
1
5.0
22.0 20.0-28.0
12 60.0 6 30.0
No. %
63
53-78
1
20.0
2
40.0
1
20.0
1
20.0
3
60.0
5 100
1
20.0
0
0
2
40.0
3
60.0
0
0
26.0 22.0-28.0
2
40.0
1
20.0
No.
%
65
50-76
1
9.1
3 27.3
6 54.5
1
9.1
10 90.9
6 54.5
6 54.5
4 36.4
1
9.1
5 45.5 6 54.5 0 0
27.0 21.0-68.9
5 45.5 0
Abbreviations: BSC, best supportive care; LDAC, low-dose cytarabine; CCR, conventional care regimen; ECOG, Eastern Cooperative Oncology Group. One patient (BSC only) had a bone marrow blast count of 13% but was included in the study based on a peripheral blast count of 20%.
564 © 2009 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by HODP. UNIVERSITARIO LA FE on May 21, 2010 from . Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.
Azacitidine v Conventional Care Regimens in Low Blast Count AML
(47%), 20 (34%), and 11 (19%) were preselected by their treating physicians to receive BSC only, LDAC, and IC, respectively. Baseline characteristics were comparable between the two treatment groups (Table 1). Median age was 70 years, and the median BM blast count was 23% in both groups. Three patients (azacitidine, n 1; BSC, n 1; LDAC, n 1) had chronic myelomonocytic leukemia (CMML) with more than 20% BM blasts. Three patients (all CMML) had a WBC count of more than 10 109/L at baseline (azacitidine, n 1; CCR, n 2). Overall, 24% of patients had an unfavorable karyotype (7/7q­ or complex; azacitidine, 25%; CCR, 22%), and 72% of patients had an intermediate karyotype (azacitidine, 69%; CCR, 74%). All patients had one blood cytopenia, and 94% had marrow multilineage dysplasia. The median number of azacitidine cycles was eight (range, one to 39 cycles), with a median cycle length of 34 days (range, 15 to 79 days). For the CCR group, the median number of LDAC cycles was 5.5 (range, one to 14 cycles), with a median cycle length of 35 days (range, 15 to 77 days), and the median number of IC cycles was 2.5 (range, one to three cycles). Median duration of BSC was 6 months (range, 2 to 19 months). Among patients who received CCR during the study, 13 received alternative active therapy after withdrawal from the study as follows: patients who received BSC during the study received LDAC (n 1), IC (n 5), and azacitidine (n 2); patients who received LDAC during the study received IC (n 1) and azacitidine (n 2); and patients who received IC during the study received LDAC (n 1) and azacitidine (n 1). Of patients who received azacitidine during the study, three received LDAC and six received IC after withdrawal from the study. Survival After a median follow-up time of 20.1 months (range, 0.03 to 38.4 months) in all patients, OS was significantly longer in the azacitidine group compared with CCR (median OS, 24.5 months; 95% CI, 14.6 months to not reached; v 16.0 months; 95% CI, 11.5 to 17.5 months, respectively; HR 0.47; 95% CI, 0.28 to 0.79; P .005; Table 2; Fig 2). The 2-year OS rate was 50% in the azacitidine group versus 16% in the CCR group (P .001). Results from the preselection analysis showed a significant difference in OS favoring azacitidine (n 36) versus BSC (n 27), with median OS of 19.1 v 13.4 months, respectively (HR 0.48; 95% CI, 0.24 to 0.94; P .03). No significant difference was observed for azacitidine (n 14) versus LDAC (n 20), with median OS of 24.5 v
Patient Survival (proportion)
1.0
0.9
0.8
0.7
0.6
50%
0.5
24.5 mo Azacitidine
0.4
16.0 mo
0.3
0.2
0.1
16%
CCR
0
5 10 15 20 25 30 35 40
Time Since Random Assignment (months)
No. of patients at risk
Azacitidine 55 43
38
26
15
10
4
1
0
CCR
58 43
36
22
6
3
0
0
0
Fig 2. Kaplan-Meier plot of overall survival in patients receiving azacitidine (n 55) or conventional care regimens (CCR; n 58). Although the flat part of the curve between 20 and 24 months appears unstable, a consistent effect was observed through these time points with a significantly higher overall survival rate in the azacitidine group versus the CCR group at month 20 (54.1% [95% CI, 38.1% to 67.5%] v 19.1% [95% CI, 8.4% to 33.2%], respectively; difference 34.9% [95% CI, 15.2% to 54.6%]; P .0005), month 24 (50.2% [95% CI, 33.8% to 64.5%] v 15.9% [95% CI, 6.2% to 29.7%], respectively; difference 34.3% [95% CI, 14.4% to 54.1%]; P .0007), and month 27 (45.6% [95% CI, 28.7% to 61.1%] v 4.8% [95% CI, 0.5% to 17.9%]; difference 40.8% [95% CI, 22.3% to 59.4%]; P .0001).
17.0 months, respectively (HR 0.37; 95% CI, 0.12 to 1.13; P .08). Median OS was not reached for azacitidine (n 5) compared with 14.2 months for IC (n 11). No evidence of statistical heterogeneity of therapeutic benefit between the CCR regimens was observed for OS (P .43). For patients who were considered unfit for IC (ie, patients preselected for BSC or LDAC), OS was significantly longer with azacitidine (n 50) versus CCR (n 47; median OS, 24.5 v 16.4 months, respectively; HR 0.44; 95% CI, 0.25 to 0.77; P .004), and the 2-year OS rate was significantly higher for azacitidine-treated patients (51% v 13%, respectively; P .0003). In patients with intermediate-risk cytogenetics, OS was significantly longer in the azacitidine group (n 38) versus the CCR group (n 43; median OS, not reached v 17.0 months, respectively; HR 0.47; 95% CI, 0.24 to 0.91; P .02), and the 2-year OS rate was higher for the azacitidine group (53% v 23%, respectively; P .02).
Table 2. OS Comparison for Azacitidine v CCR in All Patients and According to Investigator Preselection
OS Measure
All Patients
Azacitidine (n 55)
CCR (n 58)
Azacitidine v BSC Only
Azacitidine BSC Only
P (n 36) (n 27)
P
Azacitidine v Intensive
Azacitidine v LDAC
Chemotherapy Intensive
Azacitidine
LDAC
Azacitidine Chemotherapy
(n 14) (n 20) P (n 5)
(n 11)
P
OS, months
.005
.03
.08
.97
Median
24.5
16.0
19.1
13.4
24.5
17.0
NR
14.2
95% CI
14.6 to NR 11.5 to 17.5
11.2 to NR 5.2 to 17.5
18.4 to NR 14.5 to 25.8
2.7 to NR 10.8 to 24.1
HR for OS
0.47
0.48
0.37
0.97
95% CI
0.28 to 0.79
0.24 to 0.94
0.12 to 1.13
0.19 to 5.10
2-year OS rate, %
50.2
15.9
.001
46.3
0
.0001
56.3
31.8
.29
60.0
25.0
.19
95% CI
33.8 to 64.5 6.2 to 29.7
27.7 to 63.0
16.4 to 83.3 9.4 to 57.5
12.6 to 88.2 4.1 to 54.8
Abbreviations: OS, overall survival; CCR, conventional care regimen; BSC, best supportive care; LDAC, low-dose cytarabine; NR, not reached; HR, hazard ratio.
www.jco.org
© 2009 by American Society of Clinical Oncology 565
Information downloaded from jco.ascopubs.org and provided by HODP. UNIVERSITARIO LA FE on May 21, 2010 from . Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.
Fenaux et al
Table 3. Most Common Grade 3 or 4 Hematologic Adverse Events Determined by Laboratory Values Occurring in Patients Receiving Azacitidine or CCR in the Overall Safety Population, by Treatment Group and Investigator Preselection
All Patients (n 106)
Azacitidine (n 53)
CCR (n 53)
BSC Only (n 59)
Azacitidine (n 34)
BSC Only (n 25)
LDAC (n 32)
Azacitidine (n 14)
LDAC (n 18)
Intensive Chemotherapy (n 15)
Azacitidine (n 5)
Intensive Chemotherapy (n 10)
Adverse Event
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
Thrombocytopenia 48 90.6 44 83.0 31 91.2 17 68.0 13 92.9 18 100
4
80.0
9
90.0
Neutropenia
50 94.3 44 83.0 33 97.1 19 76.0 12 85.7 16
88.9
5
100
9
90.0
Anemia
30 56.6 36 67.9 18 52.9 18 72.0 10 71.4 14
77.8
2
40.0
4
40.0
Abbreviations: CCR, conventional care regimen; BSC, best supportive care; LDAC, low-dose cytarabine.
Within a subset of patients with intermediate-risk cytogenetics with normal karyotypes, OS was similar between azacitidine (n 19; median OS, 19.1 months) and CCR (n 33; median OS, 19.5 months; HR 0.95; 95% CI, 0.41 to 2.16; P .89); the 2-year OS rates were 38% v 33%, respectively (P .78). In patients with unfavorable cytogenetics, median OS in the azacitidine (n 14) and CCR (n 13) groups was 12.3 and 5.3 months, respectively (HR 0.66; 95% CI, 0.26 to 1.68; P .38), whereas the 2-year OS rate was 38% for azacitidine, with no patients surviving more than 20 months in the CCR group (P .01). Response Rates The morphologic CR rate was 18% (10 of 55 patients) in the azacitidine group and 16% (nine of 58 patients) in the CCR group (P .80). Morphologic CR was reported in three (15%) of 20 patients treated with LDAC, six (55%) of 11 patients treated with IC, and no patients treated with BSC. CR was not achieved in the three patients with CMML. Transfusion Requirements Among patients with RBC or platelet transfusion dependence at baseline, a significantly higher proportion achieved transfusion independence with azacitidine compared with CCR for RBC (41% v 18%, respectively; P .04) but not for platelets (53% v 40%, respectively; P .69); when patients preselected for IC were removed from the analysis, the respective rates for RBC transfusion independence were 44% v 15%, respectively (P .01), and the rates for platelets were 50% v 40%, respectively (P .70). In the investigator preselection analysis, only the comparison between azacitidine and LDAC for RBC transfusion independence was significant (seven of 10 patients v two of 12 patients, respectively, achieving transfusion independence; P .03). The comparison between azacitidine and IC was not possible as a result of low patient numbers. Adverse Events Two azacitidine-treated patients and five CCR-treated patients withdrew from the trial without receiving treatment and were not included in the safety analysis. Thus, the safety population included 53 patients in each group, with 25 (47%) of 53 patients assigned to BSC, 18 (34%) of 53 assigned to LDAC, and 10 (19%) of 53 assigned to IC in the CCR group. The most common grade 3 or 4 hematologic adverse events (determined by laboratory values) were thrombocytopenia, neutropenia, and anemia (Table 3). In the overall study population,
seven patients discontinued treatment as a result of adverse events, including four patients (7.3%) and three patients (5.2%) in the azacitidine and CCR groups, respectively. Patients in the azacitidine group had a lower rate of fever requiring intravenous antibiotics compared with the CCR group (0.6 v 1.1 instances per patient-year, respectively; relative risk [RR] 0.51; 95% CI, 0.29 to 0.78; P .003). When patients preselected for IC were removed from the analysis, the RR was no longer significant (0.5 v 0.7 instances per patient-year, respectively; RR 0.68; 95% CI, 0.35 to 1.24; P .18). In the investigator preselection analysis, the difference in antibiotic use was only significant for azacitidine versus LDAC (0.2 v 0.8 instances per patient-year, respectively; RR 0.21; 95% CI, 0.05 to 0.92; P .04). Azacitidine-treated patients had fewer hospital admissions compared with CCR-treated patients (3.4 v 4.3 admissions per patientyear, respectively; RR 0.79; 95% CI, 0.62 to 1.00; P .05) and fewer total number of days in hospital (26.0 v 50.9 days per patient-year; RR 0.48; 95% CI, 0.44 to 0.52; P .0001). After removing patients preselected for IC, the number of hospital admissions for azacitidineversus CCR-treated patients was 2.8 v 3.5 admissions per patient-year (RR 0.80; 95% CI, 0.59 to 1.04; P .06), and the total number of days in hospital was 20.7 v 31.6 days per patient-year (RR 0.65; 95% CI, 0.54 to 0.66; P .0001). Using the investigator preselection analysis, the number of hospitalizations per patient-year did not significantly differ between azacitidine and each of the CCR groups. However, azacitidine-treated patients required significantly fewer days in hospital per patient-year versus patients treated with BSC (P .001), LDAC (P .0001), and IC (P .0001). DISCUSSION In this analysis, patients with low BM blast count WHO-defined AML (previously classified as RAEB-t using FAB criteria) clearly benefited from azacitidine treatment compared with CCR, with half of patients in the azacitidine group still alive at 2 years compared with only 16% in the CCR group. These findings confirm previous results from a pooled analysis (three studies) of azacitidine in 27 patients from the Cancer and Leukemia Group B (CALGB) 9221 clinical trial with WHO AML (median OS, 19.3 months).30 When treated with BSC only, patients with RAEB-t have a median OS of 6 months.29,31-33 In a DuЁsseldorf MDS registry data update, patients with RAEB-t treated with BSC only (n 175; median
566 © 2009 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by HODP. UNIVERSITARIO LA FE on May 21, 2010 from . Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.
Azacitidine v Conventional Care Regimens in Low Blast Count AML
age, 71 years) had a median OS of 5 months and a 2-year OS rate of 8% (U. Germing, Personal Communication, March 2009). Among patients treated with IC in the DuЁsseldorf registry (n 88), CR was achieved in 64% and 46% of patients younger than 65 and 65 years, respectively, whereas median OS was 17 months and the 2-year OS rate was 34%, with no significant differences in OS based on age. In another experience in 106 patients with RAEB-t (median age, 59 years) treated with IC, the CR rate was 66%, and the median event-free survival duration was 30 weeks, similar to the results reported in AML patients with BM blasts more than 30% in the same study.34 Patients in the DuЁsseldorf registry treated with LDAC had a median OS of 18 months and a 2-year OS rate of 25%. Other studies of LDAC have reported median OS durations of 17 months.35,36 Also, in patients with RAEB-t treated with tipifarnib, the median OS was only 9.2 months.37 It should be considered whether the patients with AML analyzed in the present study (ie, AML with 21% to 30% BM blasts) are representative of patients with AML as a whole or whether they carry a better prognosis than patients with AML with higher BM blast percentages. Controversy remains concerning whether the natural history and responsiveness to therapy of patients with BM blasts of 20% to 30% more closely resembles that of untreated AML31,38 or advanced MDS.39,40 Several studies show no difference in OS between patients with BM blasts of 20% to 30% versus patients with BM blasts more than 30%, including patients treated with IC.34,41,42 Therefore, caution is required when comparing results from the present trial with those from broad groups of elderly patients with AML, in whom blast percentages are higher. However, the 2-year OS rate (50%) observed with azacitidine in low BM blast count (20% to 30%) AML seems higher than that reported previously in elderly patients with AML, irrespective of treatment received. Indeed, although CR rates of up to 60% have been reported in elderly patients with AML treated with IC, median OS ranged from 7 to 12 months, with 2-year OS rates of 10% to 27%.10,11,17-19,43,44 Moreover, IC is often contraindicated in elderly patients with AML, irrespective of BM blast percentage, and is generally administered to only 30% to 60% of these patients.13 Few treatment options are available for patients who cannot receive IC, and many patients still receive palliative BSC.7,13 In our study, we found that azacitidine significantly improved survival and significantly reduced time spent in hospital compared with BSC. Although LDAC significantly improved survival compared with hydroxyurea in a randomized study in elderly patients with AML, it yielded a median survival time of only 4 months and a 2-year OS rate of less than 10%.45 Similar results have been reported in other series of elderly patients with AML treated with LDAC, with a median OS of 11 months17,46,47 and a 2-year OS rate of 15%.17 We found significantly better survival with azacitidine versus CCR in patients considered unfit for IC, who represented the majority (86%) of our patients. With regard to newer treatments under evaluation in elderly patients with AML, tipifarnib failed to demonstrate any survival benefit over BSC.16 Clofarabine15,48 and cloretazine49 have reported median OS of 5 to 5.8 months, and 3.1 months, respectively, and 1-year OS rates of approximately 25% and 14%, respectively. Furthermore, both agents are associated with substantial myelosuppression,15,49,50 and clofarabine is associated with acute renal failure in up to 19% of patients.15
The survival benefit obtained with azacitidine, despite a low CR rate (18%), suggests that azacitidine can prolong survival in the absence of a CR, a finding similar to that seen in patients with intermediate-2­ and high-risk MDS in the original study population.20 Significantly more azacitidine-treated patients achieved RBC transfusion independence and azacitidine significantly reduced the number of days in hospital compared with CCR, even when excluding patients preselected for IC. These are important azacitidine-associated benefits in elderly patients in whom treatment options that reduce morbidity and the need for hospitalization are preferred. In conclusion, azacitidine prolongs survival and is well tolerated when compared with conventional and low-dose induction chemotherapy in older adult patients with WHO-defined AML with low BM blast counts (20% to 30%). The activity of azacitidine in AML with greater degrees of BM infiltration ( 30% BM blasts) is currently under investigation. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Jay Backstrom, Celgene (C); David McKenzie, Celgene (C), EMB Statistical Solutions (C); C.L. Beach, Celgene (C) Consultant or Advisory Role: Ghulam J. Mufti, Celgene (C); Eva HellstroЁm-Lindberg, Celgene (C); Guillermo Sanz, Celgene (C); Steven Gore, Celgene (C); John F. Seymour, Celgene (C); Herveґ Dombret, Celgene (C) Stock Ownership: Steven Gore, Celgene; Jay Backstrom, Celgene; Linda Zimmerman, Celgene; David McKenzie, Celgene; C.L. Beach, Celgene Honoraria: Pierre Fenaux, Roche, Amgen, Johnson & Johnson, Cephalon, MSD, GlaxoSmithKline, Celgene; Ghulam J. Mufti, Celgene; Valeria Santini, Celgene, Novartis; Norbert Gattermann, Celgene, Novartis; Ulrich Germing, Celgene; Guillermo Sanz, Celgene; Alan F. List, Celgene; John F. Seymour, Celgene; Herveґ Dombret, Celgene; Lewis R. Silverman, Celgene Research Funding: Pierre Fenaux, Roche, Celgene; Ghulam J. Mufti, Celgene; Eva HellstroЁm-Lindberg, Celgene; Norbert Gattermann, Celgene, Novartis; Ulrich Germing, Celgene; Guillermo Sanz, Celgene; Alan F. List, Celgene; Steven Gore, Celgene; John F. Seymour, Celgene expert testimony: None Other Remuneration: John F. Seymour, Celgene; Linda Zimmerman, Sr. Study Manager, Celgene; compensated position July 2000 to March 2009 AUTHOR CONTRIBUTIONS Conception and design: Pierre Fenaux, Ghulam J. Mufti, Eva HellstroЁm-Lindberg, Alan F. List, Steven Gore, John F. Seymour, Jay Backstrom, Linda Zimmerman, David McKenzie, C.L. Beach, Lewis R. Silverman Provision of study materials or patients: Pierre Fenaux, Ghulam J. Mufti, Eva HellstroЁm-Lindberg, Norbert Gattermann, Guillermo Sanz, John F. Seymour, Herveґ Dombret Collection and assembly of data: Pierre Fenaux, Ghulam J. Mufti, Eva HellstroЁm-Lindberg, Valeria Santini, Norbert Gattermann, John F. Seymour
www.jco.org
© 2009 by American Society of Clinical Oncology 567
Information downloaded from jco.ascopubs.org and provided by HODP. UNIVERSITARIO LA FE on May 21, 2010 from . Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.
Fenaux et al
Data Analysis and interpretation: Pierre Fenaux, Ghulam J. Mufti, Eva HellstroЁm-Lindberg, Valeria Santini, Norbert Gattermann, Ulrich Germing, Steven Gore, John F. Seymour, Jay Backstrom, Linda Zimmerman, David McKenzie, C.L. Beach, Lewis R. Silverman
Manuscript writing: Pierre Fenaux Final approval of manuscript: Pierre Fenaux, Ghulam J. Mufti, Eva HellstroЁm-Lindberg, Valeria Santini, Norbert Gattermann, Guillermo Sanz, Alan F. List, Steven Gore, John F. Seymour, Herveґ Dombret, Jay Backstrom, David McKenzie, Lewis R. Silverman
REFERENCES 1. Leger CS, Leitch HA, Galbraith PF, et al: Acute leukemia in patients sixty years of age and older: A twenty year single institution review. Am J Clin Oncol 32:137-141, 2009 2. Menzin J, Boulanger L, Karsten V, et al: Effects of initial treatment on survival among elderly AML patients: Findings from the SEER-Medicare database. Blood 108:1973, 2006 (suppl; abstr 1973) 3. Williams JP, Handler HL: Antibody-targeted chemotherapy for the treatment of relapsed acute myeloid leukemia. Am J Manag Care 6:S975-S985, 2000 (suppl 18) 4. Menzin J, Lang K, Earle CC, et al: The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med 162:1597-1603, 2002 5. LoЁ wenberg B, Downing JR, Burnett A: Acute myeloid leukemia. N Engl J Med 341:1051-1062, 1999 6. National Cancer Institute: Surveillance, Epidemiology, and End Results (SEER): Fast stats. http:// seer.cancer.gov/faststats 7. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology. Acute myeloid leukemia. V. 1.2009. http://www.nccn.org/ professionals/physician_gls/f_guidelines.asp 8. Appelbaum FR, Gundacker H, Head DR, et al: Age and acute myeloid leukemia. Blood 107:34813485, 2006 9. Craig CM, Schiller GJ: Acute myeloid leukemia in the elderly: Conventional and novel treatment approaches. Blood Rev 22:221-234, 2008 10. Dombret H, Raffoux E, Gardin C: Acute myeloid leukemia in the elderly. Semin Oncol 35:430438, 2008 11. Kantarjian H, O'Brien S, Cortes J, et al: Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: Predictive prognostic models for outcome. Cancer 106:10901098, 2006 12. Knipp S, Hildebrand B, KuЁ ndgen A, et al: Intensive chemotherapy is not recommended for patients aged 60 years who have myelodysplastic syndromes or acute myeloid leukemia with high-risk karyotypes. Cancer 110:345-352, 2007 13. Deschler B, de Witte T, Mertelsmann R, et al: Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: Problems and approaches. Haematologica 91:1513-1522, 2006 14. Estey EH, Thall PF, Giles FJ, et al: Gemtuzumab ozogamicin with or without interleukin 11 in patients 65 years of age or older with untreated acute myeloid leukemia and high-risk myelodysplastic syndrome: Comparison with idarubicin plus continuous-infusion, high-dose cytosine arabinoside. Blood 99:4343-4349, 2002 15. Faderl S, Ravandi F, Huang X, et al: A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood 112:1638-1645, 2008
16. Harousseau JL, Martinelli G, Jedrzejczak WW, et al: A randomized phase 3 study of tipifarnib compared to best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia (AML) in patients 70 years or older. Blood 10.1182/blood-2009-01-198093 17. Tilly H, Castaigne S, Bordessoule D, et al: Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol 8:272-279, 1990 18. Anderson JE, Kopecky KJ, Willman CL, et al: Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: A Southwest Oncology Group study. Blood 100:3869-3876, 2002 19. 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 109:5129-5135, 2007 20. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al: Efficacy of azacitidine compared with that of conventional care regimens in higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol 10:223-232, 2009 21. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189-199, 1982 22. Arber DA, Brunning RD, Orazi A, et al: Acute myeloid leukaemia with myelodysplastic-related changes, in Swerdlow SH, Campo E, Harris NL, et al (eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (ed 4). Lyon, France, International Agency for Research on Cancer, 2008 23. Harris NL, Jaffe ES, Diebold J, et al: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee MeetingAirlie House, Virginia, November 1997. J Clin Oncol 17:3835-3849, 1999 24. Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100:2292-2302, 2002 25. Brunning RD: Classification of acute leukemias. Semin Diagn Pathol 20:142-153, 2003 26. Alessandrino EP, Amadori S, Barosi G, et al: Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes: A statement from the Italian Society of Hematology. Haematologica 87:1286-1306, 2002 27. Bowen D, Culligan D, Jowitt S, et al: Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes. Br J Haematol 120:187-200, 2003 28. Cheson BD, Bennett JM, Kopecky KJ, et al: Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21:4642-4649, 2003 29. Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:20792088, 1997
30. Silverman LR, McKenzie DR, Peterson BL, et al: Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: Studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 24:3895-3903, 2006 31. Germing U, Gattermann N, Strupp C, et al: Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: A retrospective analysis of 1600 patients. Leuk Res 24:983-992, 2000 32. Greenberg P, Cos C, LeBeau MM, et al: Erratum: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 91: 1100, 1998 33. Strupp C, Gattermann N, Giagounidis A, et al: Refractory anemia with excess blasts in transformation: Analysis of reclassification according to the WHO proposals. Leuk Res 27:397-404, 2003 34. Estey E, Thall P, Beran M, et al: Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 90:2969-2977, 1997 35. Fukuhara T, Miyake T, Maekawa I, et al: Treatment with low-dose cytosine arabinoside followed by administration of macrophage colonystimulating factor prolongs the survival of patients with RAEB, RAEB-T, or leukemic phase myelodysplastic syndrome: A pilot study. Int J Hematol 71: 366-371, 2000 36. HellstroЁ m-Lindberg E, Robe` rt KH, Gahrton G, et al: A predictive model for the clinical response to low dose ara-C: A study of 102 patients with myelodysplastic syndromes or acute leukaemia. Br J Haematol 81:503-511, 1992 37. Fenaux P, Raza A, Mufti GJ, et al: A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome. Blood 109:4158-4163, 2007 38. Estey EH: Treatment of acute myeloid leukemia. Haematologica 94:10-16, 2009 39. Breccia M, Latagliata R, Carmosino I, et al: Refractory anaemia with excess of blasts in transformation re-evaluated with the WHO criteria: Identification of subgroups with different survival. Acta Haematol 117:221-225, 2007 40. Albitar M, Beran M, O'Brien S, et al: Differences between refractory anemia with excess blasts in transformation and acute myeloid leukemia. Blood 96:372-373, 2000 41. Arber DA, Stein AS, Carter NH, et al: Prognostic impact of acute myeloid leukemia classification: Importance of detection of recurring cytogenetic abnormalities and multilineage dysplasia on survival. Am J Clin Pathol 119:672-680, 2003 42. Bernstein SH, Brunetto VL, Davey FR, et al: Acute myeloid leukemia-type chemotherapy for newly diagnosed patients without antecedent cytopenias having myelodysplastic syndrome as defined by French-American-British criteria: A Cancer and Leukemia Group B study. J Clin Oncol 14:24862494, 1996 43. LoЁ wenberg B, Suciu S, Archimbaud E, et al: Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61
568 © 2009 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by HODP. UNIVERSITARIO LA FE on May 21, 2010 from . Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.
Azacitidine v Conventional Care Regimens in Low Blast Count AML
years and older with acute myeloid leukemia: Final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group. Blood 90:2952-2961, 1997 44. Rowe JM, Neuberg D, Freidenberg W, et al: A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: A trial by the Eastern Cooperative Oncology Group. Blood 103:479-485, 2004 45. 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 109:1114-1124, 2007 46. Cheson BD, Simon R: Low-dose ara-C in acute nonlymphocytic leukemia and myelodysplastic syndromes: A review of 20 years' experience. Semin Oncol 14:126-133, 1987 (suppl 1) 47. Detourmignies L, Wattel E, Laп JL, et al: Is there still a role for low-dose cytosine arabinoside in de novo acute myeloid leukemia in the elderly? A report on 77 cases. Ann Hematol 66:235-240, 1993 48. Burnett AK, Baccarani M, Johnson P, et al: A phase II study (Biov-121) of clofarabine monotherapy first line in patients aged 65 years or older
with acute myeloid leukemia for whom standard intensive chemotherapy is not considered suitable. Blood 108, 2006 (suppl; abstr 425) 49. Giles F, Rizzieri D, Karp J, et al: Cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, in patients age 60 years or older with previously untreated acute myeloid leukemia. J Clin Oncol 25:25-31, 2007 50. Erba HP, Kantarjian H, Claxton DF, et al: Phase II study of single agent clofarabine in previously untreated older adult patients with acute myelogenous leukemia (AML) unlikely to benefit from standard induction chemotherapy. Blood 112, 2008 (suppl; abstr 558)

Sign up for Alerts About Your Topic of Interest Learn about new research in your field as it becomes available. Subscribe to a JCO e-mail alert to be nofied immediately when new arcles within your area of interest are posted. Receive noficaon when: JCO releases a new issue's Table of Contents. A new issue of JCO is posted online. New arcles are published online ahead of print publicaon. New content in your subspecialty is published. An arcle is published online from an author of interest. Go to jco.org/alerts to sign up.
www.jco.org
© 2009 by American Society of Clinical Oncology 569
Information downloaded from jco.ascopubs.org and provided by HODP. UNIVERSITARIO LA FE on May 21, 2010 from . Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.

P Fenaux, GJ Mufti, E Hellström

File: azacitidine-prolongs-overall-survival-compared-with-conventional.pdf
Author: P Fenaux, GJ Mufti, E Hellström
Published: Mon Jan 18 10:16:43 2010
Pages: 8
File size: 0.23 Mb


, pages, 0 Mb

, pages, 0 Mb

God and evolution, 46 pages, 0.9 Mb

, pages, 0 Mb
Copyright © 2018 doc.uments.com