Survival after intensive therapy or clofarabine in fit older adults with acute myeloid leukemia: E2906 phase 3 trial

Key Points

• •Intensive daunorubicin and cytarabine therapy is superior to clofarabine alone in fit older adults with AML, despite similar remission rates.
• •MRD-negative remission is associated with a 48% 5-year OS; cytarabine consolidation improves outcomes in patients who are MRD-positive.

Visual Abstract

Abstract

Clofarabine is a second-generation purine nucleoside analog with encouraging reported 30-day induction mortality (IM) and complete remission (CR) or CRi (incomplete platelet recovery) rates, and represents a lower-intensity therapy for older adults with acute myeloid leukemia (AML). We evaluated long-term outcomes in a prospective phase 3 study using a noninferiority design. Patients aged ≥60 years with newly diagnosed AML and normal renal and cardiac function were randomized to standard intensive daunorubicin and cytarabine or single-agent clofarabine. The primary objective was overall survival (OS) using a weighted analysis. We incorporated prospective central testing for measurable residual disease (MRD; ≥0.1%) at remission using multiparameter flow cytometry. Among 727 patients (standard, n = 363; clofarabine, n = 364), there was no difference in CR/CRi (50%) or IM (8.5%) rates. The median follow-up was 58.6 months. In the primary analysis, OS was inferior with clofarabine (median, 10.4 vs 12.4 months [standard]; P = .04), although not in patients aged ≥70 years, with secondary AML, or unfavorable cytogenetics. Allogeneic transplantation was strongly associated with OS on multivariate analysis (HR, 0.53; P < .0001). MRD-negative remission was achieved in 41% of patients and strongly associated with 5-year OS irrespective of treatment (MRD-positive, 48.8% vs 12.2%; P = .003). In contrast, MRD-positive patients assigned to clofarabine (vs high-dose cytarabine) consolidation had significantly inferior OS. Clofarabine is inferior to standard intensive therapy despite similar remission rates. Achieving MRD-negative remission is associated with high, sustained rates of OS regardless of therapy. Increasing MRD negativity and improving outcomes among MRD-positive patients remain pressing, ongoing challenges. This trial was registered at www.clinicaltrials.gov as NCT02085408.

Introduction

Intensive therapy with curative intent using cytarabine and daunorubicin (7+3 regimen), followed by cytarabine-based consolidation, has long been the standard for fit (induction-eligible) older (aged ≥60 years) adults with acute myeloid leukemia (AML). However, high 30-day induction mortality (IM) rates, historically exceeding 10% to 15%, especially in patients aged ≥70 years,^1,2 have limited its application.^3,4 In addition to toxicity concerns, efficacy is markedly diminished in older adults with unfavorable-risk cytogenetics, with observed complete remission (CR) or CR with incomplete platelet recovery (CRi) rates of only 30% and significantly shorter median survival.⁵ The median disease-free survival (DFS) after intensive therapy in older adults is historically short (<6-8 months), with 2-year and 5-year continuous remission rates of 25% and <15%, respectively^1,6,7

Clofarabine is a rationally designed, second-generation purine nucleoside analog with more favorable intracellular pharmacokinetic and pharmacodynamic properties than fludarabine phosphate and cladribine,8, 9, 10 and has been reported to have significant single-agent activity in acute leukemia.¹¹ In older adults with AML deemed unsuitable for intensive therapy, a combined rate of CR and CRi of 48% has been reported, including in those with adverse-risk cytogenetics, with an IM rate of 9%,^12,13 suggesting it may retain efficacy and also be better tolerated in adverse-risk AML. It therefore represents an attractive, potentially lower-intensity candidate therapy for study in this population.

The ECOG-ACRIN Cancer Research Group (E-A) E2906 randomized trial was primarily designed to prospectively compare intensive 7+3 chemotherapy in fit older adults with the putatively less intensive clofarabine regimen given as a single agent, selected based on its efficacy in robust phase 2 studies. The study used a noninferiority design with superiority alternative. To further inform our understanding of relapse after remission in this population, prospective central measurable residual disease (MRD) evaluation was incorporated. Patients with an HLA-matched donor were encouraged to proceed to allogeneic hematopoietic cell transplantation (allo-HCT), and a maintenance randomization to decitabine was offered to patients in remission who did not undergo transplantation. We incorporated prospective patient-reported health-related quality of life (HRQoL) and geriatric assessments (GA).

This report focuses on the primary survival outcomes following 7+3 or clofarabine therapy, describing remission rates, MRD assessment, DFS, and overall survival (OS) with 5 years of follow-up.

Methods

Eligibility

The E-A E2906 study was an open-label, randomized phase 3 trial for patients aged ≥60 years with newly diagnosed AML. AML arising from an antecedent hematologic disorder (ie, secondary AML [sAML] after prior myelodysplastic syndrome or myeloproliferative neoplasm) or after prior exposure to chemotherapy or radiation therapy (ie, therapy-related AML [tAML]) was allowed, although prior use of low-dose cytarabine or hypomethylating agents (azacitidine and decitabine) was excluded. Eligibility included an ECOG performance status ≤3 (≤2 for patients aged ≥70 years) and adequate organ function, including left ventricular ejection fraction ≥45%, and serum creatinine ≤1.0 mg/dL (or calculated glomerular filtration rate [GFR] of ≥60 mL/min; www.mdrd.com).

Procedures and outcomes

Patients were randomized 1:1 to standard therapy (arm A: cytarabine 100 mg/m² per day for 7 days by 24-hour continuous infusion, and daunorubicin 60 mg/m² daily for 3 days), or single-agent clofarabine (arm B: 30 mg/m² daily for 5 days); age (60-69 vs ≥70 years) and presence of either tAML or sAML were used as stratification criteria at randomization. Patients with persistent AML on day 14 bone marrow (BM) biopsy were eligible to receive a second cycle of induction therapy (reinduction: arm A, identical 7+3 after day 14; or arm B, clofarabine 20 mg/m² daily for 5 days starting after day 21). Patient-reported HRQoL was assessed prospectively using the Functional Assessment of Cancer Therapy–Leukemia scale and the Functional Assessment of Cancer Therapy–Fatigue subscale, as well as GA parameters of independent function and comorbidity.

Response criteria were consistent with revised recommendations of the International Working Group.¹⁴ CR required absence of leukemic blasts and recovery of peripheral blood (PB) counts (absolute neutrophil count of ≥1.0 x 10⁹/L and platelet count of ≥100 × 10⁹/L); CRi allowed for platelet recovery counts of 50 × 10⁹/L to 99 × 10⁹/L.

Central review of pathology and cytogenetics, with central FLT3-ITD and MRD assessment

Diagnostic BM or PB samples were submitted at registration and at the time of achieving CR/CRi to the E-A Leukemia Translational Research Laboratory (LTRL; coauthors E.P., J.R., F.G.-B.), and AML diagnosis was confirmed by central pathology review (coauthor D.A.A.). Conventional cytogenetic studies were performed locally, and karyotypes centrally reviewed by the E-A Cytogenetics Committee (coauthor Y.Z.) and assigned to risk categories according to the European LeukemiaNet 2017 guidelines,¹⁵ incorporating modifications in the updated classification of the UK National Cancer Research Institute Adult Leukaemia Working Group.¹⁶

Central MRD assessment was performed in the LTRL (coauthor E.P.) using 6-color multiparameter flow cytometry on remission BM samples (collected within ±6 days of CR/CRi confirmation) based on the leukemia-associated immunophenotype (LAIP) established at diagnosis, consistent with consensus criteria.¹⁷ Details are included in the supplemental Materials under “MRD Testing.” MRD positivity was defined as ≥1 × 10⁻³ LAIP-positive cells (ie, MRD-negative <0.1%). All patients who achieved CR or CRi and had a BM specimen submitted were evaluated for MRD status, although patients with acute monocytic leukemia were excluded due to unsuitable LAIP features, as were samples accrued to trial sites in Israel due to logistical considerations. Antibodies considered suitable for monitoring of MRD were those that (1) distinguished leukemic blasts from normal precursors (eg, lack of CD34 expression by CD117⁺ myeloblasts); (2) detected expression of lineage-foreign markers (eg, lymphoid antigens expressed on the leukemic myeloblasts such as CD19, CD7, CD5); (3) detected altered density of lineage-committed and lineage-uncommitted antigens (eg, CD45 on all leukemic cells, CD33 or CD11a); or (4) asynchronous expression of antigens, including stem cell antigens (eg, CD123, CD25). FLT3-ITD testing was performed centrally on baseline samples at the LTRL as previously described (E.P. and J.R.).¹⁸

Consolidation therapy

Patients achieving CR or CRi were assigned to receive 2 cycles of consolidation therapy at ∼4-week intervals. Patients in arm A were assigned to standard arm C consolidation using age-adjusted high-dose cytarabine, as previously reported^5,19 (aged 60-69, 1.5 g/m² every 12 hours for 6 days; aged ≥70, once daily). Patients in arm B were assigned to arm D consolidation, using single-agent clofarabine (20 mg/m² daily for 5 days). Supportive care details are included in the supplemental Appendix.

allo-HCT using a reduced-intensity conditioning regimen from an HLA-matched donor²⁰ was offered on study arm G if CR/CRi or morphologic leukemia-free state (MLFS) was achieved. Patients who remained in confirmed CR/CRi after consolidation and did not proceed to allo-HCT were eligible for voluntary participation in a nonblinded 1:1 randomized phase 2 study of observation vs maintenance with abbreviated decitabine (20 mg/m² daily for 3 days, administered every 4 weeks for 1 year).

This report focuses on the primary objective. Details of allo-HCT and maintenance decitabine arms will be reported separately, along with the prospective GA and HRQoL assessments.

Study end points and statistical analysis

The primary objective was OS (time from randomization to death from any cause) using intention-to-treat analysis. A noninferiority design with superiority alternative was incorporated in the protocol study design and constructed using partial likelihood estimate based on the weighted Cox regression analysis21, 22, 23; if noninferior, clofarabine superiority analysis would be performed. The null hypothesis is that the hazard ratio (HR) for clofarabine/standard is ≥1.12, and the alternative HR for clofarabine/standard is ≤0.86. The target accrual was 747 participants, providing ∼80% power to reject the null hypothesis.

Weighted analyses were used to examine the induction treatment effects on OS because of the potential confounding effect of participation in the study of decitabine maintenance therapy. Additional details of statistical analysis and study conduct and monitoring are included in supplemental Appendix (supplemental Statistical Design and Analysis).

The study was initiated in January 2011 and continued through February 2015 (N = 727) when a significant OS advantage for standard therapy was detected by the independent E-A data monitoring committee. At that time, accrual was halted and 10 active patients receiving clofarabine (arms B and D) were transitioned to standard therapy. All participants who were alive were followed up for 5 years after the completion of protocol therapy.

Results

A total of 727 patients (median age, 68 years [range, 60-86]) were randomized and included in this analysis. Patient demographics and disease characteristics were well balanced between arms, with the exception that patients receiving standard therapy were more likely to have a baseline hemoglobin of ≥10 g/dL and white blood cell count of ≥10.0 x10⁹/L (P = .01 and P = .05, respectively; Table 1). The CONSORT diagram is illustrated in Figure 1. A total of 166 patients subsequently underwent allo-HCT at a median of 4.5 months (range, 2-41) after randomization. Of these, 72 patients were prospectively registered to protocol arm G (of whom 71 patients underwent protocol-defined reduced-intensity conditioning allo-HCT), and an additional 95 patients who received allo-HCT off study in first remission or MLFS. All patients, including 30 ineligible and 10 patients who did not start induction therapy, were included in the primary efficacy analysis.

Table 1.

Baseline characteristics of patients

	Standard (n = 363)		Clofarabine (n = 364)		Total (N = 727)
	n	%	n	%	n	%
Age, y
60-69	221	60.9	228	62.6	449	61.8
≥70	142	39.1	136	37.4	278	38.2
Sex
Male	201	55.4	213	58.5	414	56.9
Female	162	44.6	151	41.5	313	43.1
ECOG performance status
0	98	27.0	100	27.5	198	27.2
1	199	54.8	201	55.2	400	55.0
2	61	16.8	56	15.4	117	16.1
3	4	1.1	7	1.9	11	1.5
Missing	1	0.3	0	0	1	0.1
Peripheral WBC count (×109/L)
<10.0	230	63.4	257	70.6	487	67.0
≥10.0	132	36.4	107	29.4	239	32.9
Missing	1	0.3	0	0	1	0.1
Hemoglobin (g/dL)
<10	276	76.0	306	84.1	582	80.1
≥10	84	23.1	58	15.9	142	19.5
Missing	3	0.8	0	0	3	0.4
Platelet count (×103/mm3)
<50 000	159	43.8	169	46.4	328	45.1
≥50 000	202	55.6	195	53.6	397	54.6
Missing	2	0.6	0	0	2	0.3
Cytogenetics risk group
Favorable	9	2.5	16	4.4	25	3.4
Intermediate	216	59.5	199	54.7	415	57.1
Unfavorable/adverse	100	27.5	107	29.4	207	28.5
Missing	38	10.5	42	11.5	80	11.0
tAML
No	321	88.4	325	89.3	646	88.9
Yes	42	11.6	39	10.7	81	11.1
Previous AHD
No	305	84.0	299	82.1	604	83.1
Yes	58	16.0	65	17.9	123	16.9
FLT3-ITD
Wild-type	249	68.6	230	63.2	479	65.9
Mutated	35	9.6	39	10.7	74	10.2
Missing	79	21.8	95	26.1	174	23.9

AHD, antecedent hematologic disorder; WBC, white blood cell.

Figure 1.

CONSORT diagram.

Response to induction therapy

There was no difference in CR rates (45%) between treatment arms (standard, n = 162 [44.6%]; clofarabine, n = 165 [45.3%]). Further, 38 patients (standard, n = 20; clofarabine, n = 18) achieved CRi, resulting in a combined CR/CRi rate of 50.2%. In addition, 51 patients (7%) achieved MLFS (standard, 6.6%; clofarabine, 7.4%). There was no difference in time to achieve CR/CRi (median, 39 days [standard] vs 42 days [clofarabine]; P = .43), although patients randomized to clofarabine more frequently received a second induction cycle (41.1% vs 30.3% on standard arm; P = .003). The presence of FLT3-ITD was the only factor associated with differential CR/CRi rates between treatment arms, favoring standard therapy (71.4% vs 43.6%; P = .02). Among 207 patients with unfavorable- or adverse-risk cytogenetics, the CR/CRi rate was higher after receiving clofarabine (43.9% vs 31.0% [standard]; P = .06; Table 2).

Table 2.

CR/CRi analysis

	Total		CR + CRi				P value
			Nonresponder		Responder
	n	%	n	%	n	%
Age, 60-69 y
Standard	221	100	101	45.7	120	54.3	.51
Clofarabine	228	100	112	49.1	116	50.9
Age, ≥70 y
Standard	142	100	80	56.3	62	43.7	.40
Clofarabine	136	100	69	50.7	67	49.3
Favorable-risk cytogenetics
Standard	9	100	2	22.2	7	77.8	1.00
Clofarabine	16	100	5	31.3	11	68.8
Intermediate-risk cytogenetics
Standard	216	100	83	38.4	133	61.6	.11
Clofarabine	199	100	92	46.2	107	53.8
Adverse-/unfavorable-risk cytogenetics
Standard	100	100	69	69.0	31	31.0	.06
Clofarabine	107	100	60	56.1	47	43.9
No tAML
Standard	321	100	158	49.2	163	50.8	.94
Clofarabine	325	100	161	49.5	164	50.5
tAML
Standard	42	100	23	54.8	19	45.2	.83
Clofarabine	39	100	20	51.3	19	48.7
No AHD
Standard	305	100	142	46.6	163	53.4	1.00
Clofarabine	299	100	140	46.8	159	53.2
AHD
Standard	58	100	39	67.2	19	32.8	.71
Clofarabine	65	100	41	63.1	24	36.9
FLT3-ITD wild-type
Standard	249	100	126	50.6	123	49.4	.86
Clofarabine	230	100	114	49.6	116	50.4
FLT3-ITD mutated
Standard	35	100	10	28.6	25	71.4	.02
Clofarabine	39	100	22	56.4	17	43.6
Total
Standard	363	100	181	49.9	182	50.1	1.00
Clofarabine	364	100	181	49.7	183	50.3

AHD, antecedent hematologic disorder.

MRD

A total of 161 patients who achieved CR/CRi (49.2% of the CR/CRi cohort) were evaluable for MRD assessment (see “Methods”). Submission of follow-up specimens at remission assessment was not mandatory in this trial, explaining the low number of posttreatment specimens received by the central laboratory; and patients without evaluable specimens were excluded from the MRD analysis. There was no difference in baseline clinical or disease characteristics between MRD-evaluable vs nonevaluable patients, with the exception of median age (aged 69 vs 67 years, respectively; P = .03). MRD negativity by flow cytometry was defined as <0.1% leukemic blasts in the BM. Overall, 41% of patients achieved MRD-negative CR/CRi, and 59% remained MRD positive. On multivariate analysis, there was no association of achieving MRD-negative remission with treatment arm or other clinical or disease-related features (supplemental Table 1A-B), with exception of tAML, in which the likelihood of achieving MRD-negative remission was lower after clofarabine (P = .04). A scatterplot of MRD levels is included in supplemental Figure 6.

Consolidation therapy

A total of 318 patients in CR/CRi proceeded to assigned consolidation therapy. There was no difference between treatment arms in duration of consolidation treatment (median, 33 days; P = .14) or in rate of completion of both cycles of planned consolidation (standard, 57.7%; clofarabine, 54.7%; P = .65). After censoring patients who underwent protocol allo-HCT in first remission (including those achieving CR/CRi and MLFS), univariable analysis showed that patients who received 2 cycles of consolidation tended to have better DFS (HR, 0.67; 95% confidence interval [CI], 0.42-1.07; P = .09) and OS (HR, 0.61; 95% CI, 0.38-0.98; P = .04) compared with those who received only 1 cycle.

IM and treatment toxicity

The overall 30-day IM rate was 8.5% in both standard and clofarabine arms. The 30-day IM rates were higher among patients aged ≥70 years (10.1%) but differences between treatment arms (standard, 12.0%; clofarabine, 8.1%; P = .32) and among patients aged <70 years (P = .27) were not statistically significant.

Toxicity was determined using Common Terminology Criteria for Adverse Events criteria (supplemental Table 2). Patients receiving clofarabine experienced significantly lower grade 4 to 5 nonhematologic toxicity during induction therapy (standard, 27% vs clofarabine, 18%; P = .01) and consolidation (21% vs 7%; P < .001). There was no difference in cardiac toxicity (standard, 8.7% vs clofarabine, 6.1%; P = .2), but gastrointestinal toxicity was more frequent with standard therapy (15.7% vs clofarabine, 10.3%; P = .03), with the exception of transient grade 3/4 elevation in serum transaminases, which was an expected and reversible toxicity that occurred more commonly after clofarabine (32.2% vs 13.2% [standard]; P < .001). Hematologic toxicity was ubiquitous, and rates of grade 4 neutropenia (95% and 92%) and thrombocytopenia (96% and 94%) were similar between the 7+3 and clofarabine arms, respectively.

AML therapy and survival

OS after clofarabine was significantly inferior compared with standard therapy in the primary weighted analysis (median, 10.4 vs 12.4 months [standard]; HR, 1.22; 95% CI, 1.10-1.47; P = .04; Figure 2). Among predesignated patient subgroups, clofarabine OS was significantly inferior among patients aged 60 to 69 years (HR, 1.27; 95% CI, 1.0-1.63; P = .05), in those with de novo AML (HR, 1.27; 95% CI, 1.0-1.6; P = .05), and in patients with intermediate-risk cytogenetics (HR, 1.4; 95% CI, 1.1-1.8; P = .01; Figure 3). However, there was no significant difference in OS for patients aged ≥70 years, those with tAML, or those with adverse-risk cytogenetics. Treatment did not favor either arm for FLT3-ITD patients.

Figure 2.

Weighted Kaplan-Meier survival curves. (A) OS; (B) DFS.

Figure 3.

Weighted survival curves (Kaplan-Meier) for prespecified patient subgroups. (A) Patients aged 60 to 69 years; (B) de novo AML; (C) intermediate-risk cytogenetics; (D) adverse-risk cytogenetics.

With a median follow-up of 58.6 months among living patients, OS following standard therapy (vs clofarabine) at 1, 2, and 5 years was 51.4% (vs 44.7%), 33.5% (vs 21.9%), and 16.1% (vs 11.9%), respectively. After adjusting for other risk factors, clofarabine vs standard therapy was no longer significant on multivariate analysis for OS (HR, 1.11; 95% CI, 0.92-1.35; P = .28), with only cytogenetic risk grouping retained significance (P < .0001). To further evaluate this finding, we performed a sensitivity analysis adding allo-HCT in first remission to the model as a time-varying covariate. The results are included in Tables 3 and 4. There was a very strong association of allo-HCT with OS (HR, 0.53; 95% CI, 0.40-0.69; P < .0001). Cytogenetic risk group retained a significant impact, whereas clofarabine treatment (vs standard) remained nonsignificant for OS (HR, 1.077; 95% CI, 0.901-1.288; P = .42; Table 3).

Table 3.

Results of multivariate Cox model for OS (uncensored for allo-HCT)

Variable	HR	95% CI		P value
OS
Induction treatment, clofarabine vs standard	1.077	0.901	1.288	.4153
Sex, male vs female	1.035	0.862	1.244	.7092
Hemoglobin∗	0.958	0.890	1.032	.2587
WBC∗	1.003	0.999	1.008	.0919
Platelets∗	0.999	0.997	1.001	.2002
Cytogenetics
Favorable vs adverse risk	0.285	0.136	0.597	.0009
Intermediate vs adverse risk	0.514	0.415	0.636	<.0001
FLT3-ITD status, FLT3-ITD− vs FLT3-ITD+	0.810	0.604	1.087	.1600
allo-HCT received, yes vs no	0.530	0.407	0.691	<.0001

Age (60-69 vs >70 years), tAML, and the presence of AHD were included in the model as stratification factors.

AHD, antecedent hematologic disorder; WBC, white blood cell.

^∗Hemoglobin, WBC, and platelets were included as continuous variables.

Median DFS was 9.3 months with standard therapy vs 6.6 months with clofarabine (P = .06), and DFS rates (vs clofarabine) at 1, 2, and 5 years were 45.5% (vs 33.4%), 32.2% (vs 22.3%), and 19.0% (vs 11.4%), respectively. Adjusting for risk factors, on multivariate analysis, the difference in DFS with treatment regimen was not statistically significant (clofarabine: HR, 1.18; 95% CI, 0.88-1.58; P = .28; Table 4). Achievement of morphologic CR (vs CRi) was significantly associated with DFS (HR, 0.56; 95% CI, 0.35-0.90; P = .02), with no interaction observed between induction treatment arm and CR vs CRi rates in the model (P = .92).

Table 4.

Results of multivariate Cox model for DFS (uncensored for allo-HCT)

Variable	HR	95% CI		P value
DFS
Induction treatment, clofarabine vs standard	1.178	0.876	1.583	.2787
Induction response, CR vs CRi	0.556	0.345	0.896	.0158
Sex, male vs female	0.938	0.699	1.259	.6715
Hemoglobin∗	0.965	0.877	1.062	.4651
WBC∗	1.008	0.999	1.018	.0940
Platelets∗	0.997	0.993	1.000	.0562
Cytogenetics
Favorable vs adverse	0.465	0.205	1.052	.0660
Intermediate vs adverse	0.808	0.548	1.192	.2833
FLT3-ITD status, FLT3-ITD− vs FLT3-ITD+	1.037	0.613	1.755	.8923

Age (60-69 vs >70 years), tAML, and the presence of AHD were included in the model as stratification factors.

AHD, antecedent hematologic disorder; WBC, white blood cell.

^∗Hemoglobin, WBC, and platelets were included as continuous variables.

MRD and long-term survival

MRD status in remission was strongly associated with outcomes in the evaluable subset (Figure 4). For MRD-negative patients, OS rates at 1, 2, and 5 years were 75.3% (vs MRD-positive, 64.9%), 60.3% (vs 39.3%), and 48.8% (vs 12.2%), respectively, irrespective of treatment arm (HR, 2.35; 95% CI, 1.37-4.05; P = .002). Similarly, the DFS rates for MRD-negative patients at 1, 2, and 5 years were 66.4% (vs MRD-positive, 42.9%), 53.1% (vs 33.4%), and 36.5% (vs 10.1%), respectively, also irrespective of treatment (HR, 2.14; 95% CI, 1.22-3.76; P = .003). There was no association of treatment regimen with long-term survival for MRD-negative patients (clofarabine vs standard 7+3: HR, 0.89; 95% CI, 0.33-2.44; P = .82). In contrast, OS was significantly worse for patients in MRD-positive remission assigned to clofarabine vs standard cytarabine consolidation therapy (HR, 1.99, 95% CI, 1.07-3.71; P = .03), although the difference in DFS was not significant (HR, 1.67; 95% CI, 0.91-3.05; P = .10; Figure 5).

Figure 4.

Landmark analysis of MRD status and OS and DFS from CR/CRi. (A) OS; (B) DFS (n = 161).

Figure 5.

Outcomes (OS and DFS) from CR/CRi based on MRD status, stratified by therapy. (A) OS (n = 161). (B) DFS (n = 161).

After adjusting for other risk factors, MRD status (P = .01), tAML (P = .0005), age (P = .01), sex (P = .04), and baseline platelet counts (P = .04) remained significantly associated with OS on multivariate analysis; treatment arm (P = .94) and cytogenetic risk group (P = .32) were no longer significant. For DFS, only MRD status (P = .003), tAML (P = .004), and sex (P = .01) remained significant.

Discussion

Although designed to evaluate a potentially lower-intensity regimen based on encouraging phase 2 data,^12,13 the E2906 randomized trial failed to demonstrate lower IM or noninferior survival with clofarabine, demonstrating the central importance of randomized studies in investigating promising new agents and strategies. The superior survival observed with intensive 7+3 cytarabine and daunorubicin therapy was driven predominantly by its favorable impact in patients aged <70 years, those with de novo AML, and those with intermediate-risk cytogenetics, strongly supporting its use in these patients. Based on these results, 7+3 remains the standard-of-care therapy in these populations and an appropriate comparator for future randomized trials with robust end points²⁴ in which there is equipoise.

In contrast, OS after clofarabine was not inferior in important prespecified patient subgroups, including patients aged ≥70 years and those with tAML. As anticipated,¹² clofarabine appeared to have particular activity in the adverse cytogenetics risk group, although differences in CR/CRi (P = .06) and in OS (P = .09) did not achieve statistical significance. Importantly, liposomal daunorubicin and cytarabine (CPX-351) is now approved for patients with sAML, tAML, or myelodysplastic syndrome (MDS)-related cytogenetic changes, and represents a superior intensive therapy option based on an OS advantage compared with 7+3.²⁵

Clinical results in E2906 closely echo early reports with clofarabine^12,13; however, its use did not translate to a noninferior outcome despite achieving identical CR/CRi rates and, as anticipated, significantly less grade 4 to 5 nonhematologic toxicity. This likely relates to better-than-expected 30-day IM with standard intensive therapy and the apparent positive impact of cytarabine consolidation in MRD-positive patients. In view of these results, and other studies failing to show an advantage of clofarabine (either alone or in combination),^26,27 its further use in AML remains speculative, and clofarabine remains an investigational agent.

An important feature of this modern-era intensive therapy study is the structured surveillance and long-term follow-up in a well-defined, fit older population with normal renal function, using current supportive care strategies. The 5-year results are noteworthy, with a median survival of >12 months after intensive therapy, significantly longer than in previous published historical reports.^1,2,5,19 Similarly, 5-year survival rates exceeded expectation from previous E-A studies and compared favorably with reported results in this population from other cooperative group studies published within the past decade,^1,6,7 in which long-term OS rates of ≤15% were projected. The lower-than-predicted IM with 7+3 highlights the need for caution in basing such estimates on historic controls. Protocol guidelines for use of antimicrobial prophylaxis, myeloid growth factors, and supportive therapy likely contributed to these data.²⁸

Interestingly, cytogenetic risk remained significantly associated with long-term survival in the secondary analysis, whereas induction therapy was no longer significant. This likely reflects the impact of subsequent consolidation and maintenance therapies. In support of this notion, we identified a significant association between allo-HCT and OS (HR, 0.53; P < .0001) when included as a variable in a sensitivity analysis. These finding are in line with recent retrospective registry reports,^29,30 and we are currently performing a detailed analysis of transplant outcomes to delineate their impact in more detail. Similarly, only CR (vs CRi) retained significance for long-term DFS, supporting the goal of increasing the rate of high-quality hematologic remission in this population.

A singularly important observation from E2906 is the remarkable 48.8% 5-year survival in MRD-negative patients. In fact, MRD-negative remission was associated with improved outcomes regardless of therapy regimen. A similar beneficial impact of MRD-negative remission on 3-year risk of relapse and survival was reported in the UK NCRI AML-16 study,³¹ and the current trial extends that observation to 5 years. We acknowledge that not all AML phenotypes were amenable to MRD testing by the LAIP methodology used. In addition, the number of follow-up specimens received by the central laboratory was low, such that only approximately one-half of patients in CR/CRi were MRD evaluable in this study. Nevertheless, these results are compelling, and the development of novel strategies building on these results is warranted to improve the MRD-negative remission rate while maintaining lower IM. In particular, submission of MRD specimens should be mandatory in future AML trials, and the use of the different-from-normal approach (vs LAIP) for flow cytometric MRD assessment is also warranted.³²

A notable limitation of E2906 trial is the lack of available comprehensive genomic testing results for additional somatic leukemia driver gene mutations (beyond FLT3-ITD),³³ which hinders identification of subgroups that may (or may not) benefit to the same degree from standard therapy and also aid in interpretation of possible confounders. E2906 was concluded before the routine incorporation of next-generation sequencing–based mutation profiling; however, such profiling is currently being performed on available samples in a follow-up analysis. The incidence of FLT3-ITD mutation was lower than reported in younger adults^34,35 and was not predictive of worse long-term outcome in this older population. Nevertheless, based on more recent randomized trials, combination therapy with targeted FLT3 inhibitors (midostaurin, based on studied in younger adults,³⁵ and quizartinib³⁶) is now US Food and Drug Administration–approved options in older adults.

Consistent with our prospective study, observational studies suggest a survival benefit of intensive over less intensive therapy for eligible, fit older patients.⁴ Furthermore, we identified a strong association of CR (vs CRi) with DFS, highlighting the value of high-quality hematologic remission. Together, these observations sound a note of caution in exploring lower-intensity regimens in fit, intensive therapy–eligible older adults, particularly in the more favorable subgroups we identified (patients aged <70 years, de novo AML, intermediate-risk cytogenetics), unless consolidation with allo-HCT is planned.

Very encouraging composite CR/CRi rates and significant improvements in median survival in the Viale-A study of lower-intensity venetoclax and azacitidine therapy have changed the paradigm for patients aged ≥75 years or otherwise unfit for induction,³⁷ and these regimens have been widely adopted in practice. Conducted immediately following E2906, this trial has sparked renewed interest in exploring venetoclax-based regimens in fit older patients aged <75 years. As we demonstrated, 30-day IM rates with 7+3 in the modern era are superficially similar to those reported in Viale-A study. Prospective trials have now been initiated to compare these strategies directly in fit older patients.

Similar rates of MRD-negative remission were also reported following azacitidine and venetoclax, albeit typically occurring later in the course of therapy.³⁸ Similarly, very high rates of MRD-negative composite CRs have recently been reported with the addition of venetoclax to 7+3 in younger adults (aged <60 years), although there are no robust data on its safety in older patients yet.³⁹ It is possible, and indeed likely, that achievement of MRD-negative remission by any means will translate into a similar degree of improved long-term outcomes regardless of the regimen, as we observed with clofarabine, but it is not yet known whether the kinetics of achieving MRD-negative remission (ie, within 1-2 months vs later, depending on the therapy) are clinically important. Emphasis must again be placed on improving outcomes in those who remain MRD positive (currently the majority), who may benefit from intensified consolidation strategies, as we observed. Prospective trials such as the recently launched NCI MyeloMATCH study are evaluating newer agents and strategies (eg, maintenance with oral azacitidine⁴⁰ or targeted agents in the presence of IDH1/2 mutations⁴¹) and are essential to further improve outcomes in MRD-positive remission.

Outcomes in E2906 also differed based on well-established risk factors. These include sex in the MRD-evaluable subset, consistent with a finding described previously by our group,⁴² although in E2906 there were no significant differences in cytogenetic risk group or disease characteristics by sex (apart from tAML which was more common in women [14.1%] than men [8.9%]; P = .03). The results therefore support a more individualized treatment approach in older adults based on patient goals, comorbidities, and performance status, as well as disease characteristics (including cytogenetic risk group and tAML), to pursue potentially curative therapy and optimize long-term outcomes. Aiding this, recent studies have shown that assessment of fitness criteria for intensive therapy is feasible and straightforward at diagnosis in this population, including for patients aged >70 years.^43,44

E2906 demonstrates updated expectations for the safe achievement of MRD-negative remission and long-term survival in fit older adults with AML and highlights the enduring impact of intensive cytarabine and daunorubicin therapy for fit older adults, particularly with de novo AML and intermediate-risk cytogenetics.

Conflict-of-interest disclosure: JMF: Research Funding (institution): Takeda, Kura, Sellas, Celgene, Chorida; Advisory Board: Daiichi-Sankyo, Geron, Syndax JKA: Advisory Role/Consultant: AbbVie, Astellas Pharma, Bluebird Bio, Charm Therapeutics, Curio, Daiichi Sankyo, Dark Blue Therapeutics, Gilead, Johnson and Johnson, Kura Oncology, Kymera, Rigel, Servier, Stemline Therapeutics, Sumitomo, Syros, Treadwell Therapeutics, Orum; Data Monitoring Committee: GlycoMimetics, Kura Oncology; Research Funding (Institution): AbbVie, Agios, ALX Oncology, Aptose Biosciences, Astellas Pharma, Blossom Hill Therapeutics, Bristol Myers Squibb, Crossbow Therapeutics, Fujifilm, Immunogen, Kartos Therapeutics, Kura Oncology, Loxo, Orum, Pfizer, Takeda, Telios; Travel, Accomodations, and Expenses: Astellas Pharma, Charm Therapeutics, Daiichi Sankyo; Other Relationship(s): HMPGlobal (GDU), MDEducation, NCI, NCCN, PeerView, PER, VJ HemOnc SML: Advisory/Consultant: Geron, Astra Zeneca, Astellas, Daiichi Sankyo, Novartis, AbbVie, Amgen; Data Monitoring Committee: Marker Therapeutics HML: Consultant: CSL Behring; Speaker: Geron, Pfizer, Amgen; Data Monitoring Committee: BMS MRL: Research Support (Institution): AbbVie, Amgen, Astellas, Actinium, Pluristem, Sanofi; Speaker: Amgen, BeOne MST: Advisory: Moleculin Biotech, SDK Therapeutics; Royalties: UpToDate ZS, DFC, DAA, JMR, EP, JR, FGB, YZ, AAK, HZ, KQP, ERB, BLP, KMO, JEG, YO: no disclosures reported.