Pretransplantation Consolidation Chemotherapy Decreases Leukemia Relapse after Autologous Blood and Bone Marrow Transplants for Acute Myelogenous Leukemia in First Remission

Article Outline

• Abstract
• Introduction
• Patients and methods
  • Data Sources
  • Patients
  • Endpoints
  • Statistical Analysis
• Results
  • Patients
  • Univariate Analyses
  • Multivariate Analyses
• Discussion
• Acknowledgments
• References
• Copyright

Abstract 

Controversy exists over whether pretransplantation consolidation chemotherapy affects the outcome of subsequent autotransplantation for acute myelogenous leukemia (AML). The current study was undertaken to determine the association between previous consolidation and outcome of autotransplantation for AML in first remission. Posttransplantation outcomes of 146 patients receiving no consolidation were compared with those of 244 patients receiving standard-dose (<1 gm/m²) and 249 patients receiving high-dose (1-3 gm/m²) cytarabine, using proportional hazards regression to adjust for differences in prognostic variables. One-year transplantation-related mortality was similar among the cohorts. Five-year relapse rates were 49% (95% confidence interval CI} = 39%-58%) with no consolidation, 35% (95% CI = 29%-42%) with standard-dose cytarabine, and 40% (95% CI = 33%-48%) with high-dose cytarabine (P = .07). Five-year leukemia-free survival rates were 39% (95% CI = 30%-47%) with no consolidation, 53% (95% CI = 46%-60%) with standard-dose cytarabine, and 48% (95% CI = 40%-56%) with high-dose cytarabine (P = .03). Similarly, 5-year overall survival was better in those patients receiving consolidation: 42% (95% CI = 34%-51%) with no consolidation, 59% (95% CI = 52%-65%) with standard-dose cytarabine, and 54% (95% CI = 46%-61%) with high-dose cytarabine (P = .01). Although most patients received 1 or 2 cycles of consolidation, the number of courses had no detectable effect on transplantation outcome. In multivariate analysis, risks of relapse and treatment failure were lower in the patients receiving consolidation, especially among those patients receiving blood cell grafts. Outcomes with standard-dose and high-dose cytarabine were similar. Based on our findings, we recommend that patients with AML in first remission receive consolidation before undergoing autotransplantation.

Key words:  Autologous , Transplantation , Autotransplantation , Consolidation , Acute myelogenous leukemia

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Introduction 

Autologous hematopoietic stem cell transplantation (AuSCT) is an effective treatment for patients with acute myelogenous leukemia (AML) in first complete remission (CR) [1, 2, 3, 4, 5, 6]. Three- to 4-year leukemia-free survival (LFS) with this approach is 45%-55%. Attempts to improve these results have included ex vivo graft purging techniques [7, 8, 9], in vivo purging strategies, and posttransplantation immunologic manipulations, such as interleukin-2 or infusion of lymphokine-activated killer cells [10, 11, 12].

Pretransplantation consolidation chemotherapy, often with high-dose cytarabine, is routinely administered before high-dose conditioning. The benefits of such a strategy are unclear, however. It is possible that consolidation chemotherapy before transplantation may reduce the leukemic cell burden and thereby improve transplantation outcome by reducing posttransplantation relapse [5, 13]. Alternatively, intensive consolidation chemotherapy may result in toxicities severe enough to preclude transplantation or may increase the risk of transplantation-related morbidity and mortality. In the setting of allogeneic stem cell transplantation for AML in first CR, we previously found that pretransplantation cytarabine consolidation did not favorably influence outcome compared with no pretransplantation consolidation [14]. This lack of benefit may be attributable to potent graft-versus-leukemia (GVL) effects of allogeneic transplantation, which may overcome or be less influenced by pretreatment patient- or disease-related characteristics or greater amounts of residual disease. The lack of such a GVL effect after autotransplantation may make intensive pretransplantation consolidation chemotherapy important. This study was designed to compare the outcome of AuSCT recipients receiving either no pretransplantation consolidation, standard-dose cytarabine consolidation, or high-dose cytarabine consolidation before high-dose therapy.

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Patients and methods 

Data Sources 

The Autologous Blood and Marrow Transplant Registry (ABMTR) is a voluntary working group of more than 250 transplantation centers, primarily in North and South America, which contribute detailed data on their autologous transplantation recipient to a Statistical Center at the Health Policy Institute of the Medical College of Wisconsin. Participating centers are required to register all transplantations consecutively; compliance is monitored by on-site audits. The database of the ABMTR includes >50% of all autologous transplantations performed in North and South America since 1990. Patients are followed longitudinally, with yearly follow-up. Computerized checks for errors, physician review of submitted data, and on-site audits of participating centers ensure the quality of the data.

The ABMTR collects data at 2 levels: registration and research. Registration data include disease type, age, sex, pretransplantation disease stage and chemotherapy responsiveness, date of diagnosis, graft type (bone marrow– and/or blood-derived stem cells), high-dose conditioning regimen, posttransplantation disease progression and survival, development of a new malignancy, and cause of death. Requests for data on progression or death for registered patients are at 6-month intervals. All ABMTR teams contribute registration data. Research data are collected on subsets of registered patients and include comprehensive pretransplantation and posttransplantation clinical information.

Patients 

This study included 639 patients undergoing AuSCT for AML in first CR between 1989 and 1998, for whom comprehensive research data were reported to the ABMTR. During the study period, registration data were submitted for an additional 731 patients receiving AuSCT for AML in first CR. Demographics and survival of these patients were similar to those of the study population. A total of 146 patients received no pretransplantation consolidation, 244 received standard-dose cytarabine consolidation, and 249 received high-dose cytarabine consolidation before transplantation. Additional drugs were included in the consolidation regimens of 220 (90%) patients receiving standard-dose cytarabine and 192 (77%) of the patients receiving high-dose cytarabine. Standard-dose cytarabine was defined as <1 g/m²/dose; high-dose cytarabine, as 1-3 g/m²/dose. Chemotherapy given for mobilization was counted as consolidation. The median follow-up of survivors was 49 months, including 57 months for those receiving no pretransplantation consolidation, 52 months for those receiving standard-dose cytarabine, and 36 months for those receiving high-dose cytarabine.

Cytogenetic abnormalities were divided into those associated with good, intermediate, or poor prognosis. Cytogenetic abnormalities with good prognosis included t(8;21) with or without other abnormalities, t(15;17) with or without other abnormalities, and inv or del(16) with or without other abnormalities. Cytogenetic abnormalities with intermediate prognosis included trisomy 8 with or without other abnormalities, trisomy 21 with or without other abnormalities, t(6;9) with or without other abnormalities, other translocations, other numerical abnormalities, and other structural abnormalities. Cytogenetic abnormalities with poor prognosis included t(9;22) with or without other abnormalities; −7 or del(7) with or without other abnormalities, and del(11) with or without other abnormalities and complex karyotypes [15]. Patients with cytogenetic abnormalities of both good and poor prognosis were considered to be in the poor prognosis group.

Endpoints 

Primary study endpoints were transplantation-related mortality (TRM), clinical leukemia relapse (hematologic and extramedullary), LFS, and overall survival. TRM was defined as death during continuous CR posttransplantation. Relapse was defined as clinical or hematologic leukemia recurrence. For analyses of LFS, failures were clinical or hematologic relapses or deaths from any cause; patients alive and in complete remission were censored at time of last follow-up. For analysis of overall survival, failure was death from any cause; surviving patients were censored at the date of last contact.

Statistical Analysis 

Patient-, disease-, and transplantation-related variables for patients receiving no postremission therapy, those receiving standard-dose cytarabine postremission therapy, and those receiving high-dose cytarabine postremission therapy were compared using the χ² statistic for categorical variables and the Kruskal-Wallis test for continuous variables. Univariate probabilities of LFS and survival were calculated using the Kaplan-Meier estimator; the log-rank test was used for univariate comparisons. Probabilities of TRM and leukemia relapse were calculated using cumulative incidence curves to accommodate competing risks [16]. Assessment of potential risk factors for outcomes of interest were evaluated through multivariate analyses using Cox proportional hazards regression [17]. The variables considered in multivariable analysis are listed in Table 1.

Table 1. Variables Tested in Cox Proportional Hazards Regression Models

Main effect variable⁎:

Type of pretransplantation consolidation therapy: none versus standard or high-dose cytarabine

Patient-related variables:

Age at transplant: <40 years versus ≥40 years

Sex: female versus male

Karnofsky performance status pretransplantation: <90% versus ≥90% versus missing

Disease-related variables at diagnosis:

FAB subtype: M1,M2 versus M3 versus M4 versus M5–M7 versus other/unclassified

WBC at diagnosis: ≤10×109/L versus 10-100×109/L versus ≥100×109/L versus missing

Cytogenetics: good prognosis versus intermediate prognosis versus poor prognosis versus no abnormalities versus unknown

Disease-related variables at transplantation:

Extramedullary disease at diagnosis: yes versus no

Previous myelodysplastic syndrome: yes versus no

Induction therapy: 1 cycle standard-dose Ara-C ± other versus >1 cycle standard-dose Ara-C ±other versus 1 cycle high-dose Ara-C ±other versus >1 cycle high-dose Ara-C ± other versus 1 cycle other induction therapy versus >1 cycle other induction therapy

Additional drugs for consolidation: yes versus no

Time from diagnosis to CR1: ≤2 months versus >2 months versus missing

Cycles of chemotherapy to achieve CR1: 1 versus >1 versus missing

Consolidation chemotherapy cycles after CR1: 1 versus 2 versus >2 versus missing

Time from diagnosis to transplantation

Time from CR1 to harvest: ≤3 months versus >3 months versus missing

Time from CR1 to transplant: ≤3 months versus >3 months versus missing

Treatment-related:

Source of stem cell: BM versus PBSC

Conditioning regimen: CyTBI ± other versus BuCyVP16 ± other versus BuCy ± other versus others

Year of transplantation: 1989-1994 versus 1995-1998

Induction of GVHD: yes versus no versus missing

Growth factors posttransplantation: yes versus no

FAB indicates French-American-British classification; WBC, white blood cell count; BM, bone marrow; PBSC, peripheral blood stem cells; CR, complete remission; Bu, busulfan; Cy, cyclophosphamide; TBI, total body irradiation; VP16, etoposide; GVHD, graft-versus-host disease; GF, growth factors.

First, we compared the likelihood from a model stratified on pretransplantation consolidation therapy with that from a model with different risk coefficients for each pretransplantation consolidation therapy. The likelihood ratio test constructed from these models determined whether there was any interaction between pretransplantation consolidation therapy and the factor being examined. When the likelihood ratio test was significant, an interaction term was added to the model. After determining interaction terms, we next tested for proportional hazards for each factor in the Cox model using time-dependent covariates. When this indicated differential effects over time (nonproportional hazards), we constructed models breaking the posttransplantation course into 2 time periods, using the maximized partial likelihood method to find the most appropriate break point. After the foregoing modeling of time-varying effects, we constructed the final multivariate model using a forward stepwise model selection approach. Each model contained the main effect for pretransplantation consolidation therapy (no pretransplantation consolidation vs standard-dose cytarabine vs high-dose cytarabine). However, risks associated with high- and standard-dose cytarabine were virtually identical in all analyses, and so the final models show only the relative risk (RR) of each outcome for patients receiving any consolidation versus those receiving no consolidation. There was a significant interaction between the graft type and the effect of consolidation, meaning that previous consolidation had a different effect depending on whether the patient received a bone marrow or peripheral stem cell graft; thus, the comparisons are stratified based on graft type. Factors that were significant at a 5% level were kept in the final model. Because the final models included previous myelodysplastic syndrome as a significant factor, 7 patients with unknown previous myelodysplastic syndrome were excluded in all multivariate analyses. Examination for center effects used a random-effects or frailty model [18]. We found no evidence of correlation between center effects and any of the outcomes. All P values are 2-sided.

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Results 

Patients 

Patient-, disease- and transplantation-related variables are given in Table 2. The median age of the patients receiving standard-dose cytarabine consolidation was 24 years, younger than those receiving either no consolidation or high-dose cytarabine consolidation. There was no significant difference in gender distribution. A greater percentage of patients receiving high-dose cytarabine had a pretransplantation Karnofsky score <90%. The median white blood cell count at diagnosis was lower in the no pretransplantation consolidation group than in the standard- and high-dose cytarabine groups. There were no differences in the distribution of good, intermediate, or poor prognosis cytogenetics among the 3 groups. Approximately 30% of the patients in each group had normal cytogenetics, and 30% had unknown karyotypes. A higher percentage of patients receiving either no consolidation or standard-dose cytarabine had extramedullary disease compared with those receiving high-dose cytarabine. There were no differences among the groups in the percentage of patients with previous history of myelodysplastic syndrome. Patients receiving high-dose cytarabine were more likely to receive only 1 cycle of pretransplantation consolidation than those receiving standard-dose cytarabine. The time from diagnosis to first CR was longer in the patients receiving no consolidation. Not unexpectedly, the time between achieving CR and transplantation was longer for the patients who received consolidation. More patients not receiving consolidation or receiving standard-dose cytarabine had bone marrow as the source of stem cells compared with those receiving high-dose cytarabine. Purging the graft to remove leukemia cells was more likely to be done for the patients who did not receive consolidation. The patients who received consolidation with high-dose cytarabine were more likely to receive either granulocyte or granulocyte-macrophage colony-stimulating factor to promote hematopoietic recovery. Moreover, 97% of patients receiving pretransplantation consolidation received growth factors for harvesting.

Table 2. Characteristics of Patients Receiving Autologous Transplantation for AML in First Complete Remission by Cytarabine (Ara-C) Pretransplantation Consolidation Therapy

	No Pretransplantation Consolidation		Standard-Dose Ara-C		High-Dose Ara-C
Variable	No. evaluable	n (%)	No. evaluable	n (%)	No. evaluable	n (%)	P value⁎
Number of patients		146		244		249	—
Age, median (range), years	146	30(1-70)	244	24(1-71)	249	38(1-69)	<.001
Age by decade, years	146		244		249		<.001
<10		35(24)		63(26)		24(10)
10-19		18(12)		42(17)		28(11)
20-29		18(12)		33(14)		34(13)
30-39		25(17)		33(14)		60(24)
40-49		20(14)		43(17)		44(18)
≥50		30(21)		30(12)		59(24)
Male	146	67(46)	244	116(48)	249	131(53)	.356
Karnofsky score pretransplantation <90	135	16(12)	239	33(14)	244	56(23)	.006
FAB subtype	146		244		249		.205
Unclassified		13(9)		9(4)		10(4)
M1		20(14)		27(11)		34(14)
M2		29(20)		76(31)		64(26)
M3		16(11)		18(7)		22(9)
M4		25(17)		57(24)		64(26)
M5		30(21)		40(16)		36(14)
M6		6(4)		4(2)		6(2)
M7		5(3)		8(3)		7(3)
Other		2(1)		5(2)		6(2)
WBC at diagnosis, median(range), ×109/L	135	11(<1-453)	209	14(1-418)	213	15(<1-255)	.557
WBC at diagnosis	135		209		213		.824
≤10 × 109/L		65(48)		91(44)		94(44)
10-100 × 109/L		61(45)		99(47)		98(46)
≥100 × 109/L		9(7)		19(9)		21(10)
Cytogenetics†	146		244		249		.381
No abnormalities		45(31)		66(27)		85(34)
Good prognosis		15(10)		33(14)		30(12)
Intermediate prognosis		31(21)		59(24)		52(21)
Poor prognosis		10(7)		8(3)		17(7)
Unknown		45(31)		78(32)		65(26)
Extramedullary disease at diagnosis	146	25(17)	244	37(15)	249	18(7)	.005
Previous myelodysplastic syndrome	144	9(6)	241	8(3)	247	6(2)	.142
Induction therapy	138		236		235		<.001
1 cycle standard-dose Ara-C ± other		29(21)		120(51)		109(46)
>1 cycle standard-dose Ara-C ± other		62(45)		76(32)		40(17)
1 cycle high-dose Ara-C ± other		19(14)		3(1)		53(23)
>1 cycle high-dose Ara-C ± other		4(3)		2(1)		17(7)
1 cycle other therapy		18(13)		26(11)		10(4)
>1 cycle other therapy		6(4)		9(4)		6(3)
Additional drugs for consolidation‡	NA		244	220(90)	249	192(77)	<.001§
Time from diagnosis to CR1, median (range), months	145	2(<1-7)	241	1(<1-6)	240	1(<1-7)	<.001
Time from diagnosis to CR1 >2 months	145	53(37)	241	71(29)	240	43(18)	<.001
Cycles of chemotherapy to achieve CR1	138		236		235		<.001
1		66(48)		149(63)		172(73)
2		38(27)		65(27)		50(22)
3		8(6)		18(8)		10(4)
≥4		26(19)		4(2)		3(1)
Consolidation chemotherapy cycles after CR1¶	NA		223		207		<0.001§
1				98(44)		123(59)
2				93(42)		51(25)
>2				32(14)		33(16)
Time from diagnosis to transplantation median (range), months	146	4(2-16)	244	5(3-48)	249	6(2-20)	<.001
Time from CR1 to harvest, median (range), months	140	2(<1-5)	235	3(<1-10)	233	3(<1-10)	<.001
Time from CR1 to transplantation, median (range), months	144	2(<1-8)	235	4(<1-11)	237	4(<1-11)	<.001
Source of stem cells	146		244		249		<.001
BM		120(82)		180(74)		111(45)
Peripheral blood		16(11)		55(22)		108(43)
BM + peripheral blood		10(7)		9(4)		30(12)
Purging	146	121(83)	244	92(38)	249	39(16)	<.001
Agents used for purging							—
Monoclonal antibody		3(2)		1(1)		3(8)
4-hydroperoxycyclophosphamide		88(73)		79(86)		26(67)
Mafosfamide		0		3(3)		1(2)
Other#		11(9)		6(7)		3(8)
Conditioning regimen	146		244		249		.001
CyTBI ± other		13(9)		29(12)		23(9)
BuCyVP16 ± other		4(3)		18(7)		18(7)
BuCy ± other(not VP16)		107(73)		146(60)		131(53)
Other		22(15)		51(21)		77(31)
Year of transplant	146		244		249		<.001
1989		24(16)		16(7)		2(1)
1990		14(9)		17(7)		10(4)
1991		13(9)		35(14)		23(9)
1992		23(16)		37(15)		21(9)
1993		33(23)		27(11)		30(12)
1994		16(11)		40(16)		17(7)
1995		10(7)		28(11)		30(12)
1996		9(6)		16(7)		37(15)
1997		4(3)		17(7)		38(15)
1998		0		11(5)		41(16)
Induction of GVHD/immunotherapy	143	14(10)	220	16(7)	238	5(2)	.004
G-CSF or GM-CSF given within 7-days posttransplantation	146	24(16)	244	67(27)	249	139(56)	<.001

AML indicates acute myelogenous leukemia; Ara-C, cytosine arabinoside; FAB, French-American-British classification; WBC, white blood cell count; BM, bone marrow; CR, complete remission; NA, not applicable; SDAC, standard-dose Ara-C; HDAC, high-dose Ara-C; Bu, busulfan; IL-2, interleukin-2; Cy, cyclophosphamide; TBI, total body irradiation; VP16, etoposide; GF, growth factors; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor.

Univariate Analyses 

Univariate comparisons of outcomes are given in Table 3. One-year TRM rates were similar among the 3 treatment groups (Figure 1A). The 5-year relapse rate was 10% lower in the patients receiving consolidation than in those not receiving consolidation (Figure 1B). The 5-year LFS and overall survival were significantly higher in those receiving consolidation than in those not receiving consolidation.

Table 3. Univariate Analysis of Transplantation Outcomes in Patients Receiving Autologous Transplantation for AML in First Complete Remission by Ara-C Pretransplantation Consolidation Therapy

	No Pretransplantation Consolidation		Standard-Dose Ara-C		High-Dose Ara-C
Outcome event	No. evaluable	Probability (95% CI)⁎	No. evaluable	Probability (95% CI)⁎	No. evaluable	Probability (95% CI)⁎	P Value†
100-day mortality	146	12(8-18)	244	10(6-14)	249	6(3-9)	.098
TRM	144		238		243
At 1 year		8(4-13)		9(6-13)		6(4-10)	.451‡
At 3 years		10(6-16)		11(7-15)		8(5-12)	.641‡
At 5 years		12(7-18)		11(8-16)		11(7-16)	.987‡
Relapse	144		238		243
At 1 year		37(29-46)		25(20-31)		28(22-34)	.064‡
At 3 years		47(37-56)		34(28-41)		37(30-44)	.090‡
At 5 years		49(39-58)		35(29-42)		40(33-48)	.072‡
LFS	144		238		243		.020†
At 1 year		54(46-62)		65(59-71)		66(60-72)	.047‡
At 3 years		42(34-51)		55(49-61)		55(48-61)	.034‡
At 5 years		39(30-47)		53(46-60)		48(40-56)	.033‡
Overall survival	146		244		249		.007†
At 1 year		63(55-71)		73(68-79)		75(69-80)	.050‡
At 3 years		46(38-54)		61(55-67)		63(56-69)	.005‡
At 5 years		42(34-51)		59(52-65)		54(46-61)	.012‡

AML indicates acute myelogenous leukemia; Ara-C, cytosine arabinoside; TRM, treatment- related mortality; LFS, leukemia-free survival; CI, confidence interval.

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• Figure 1. 

  Cumulative incidences of TRM (A) and relapse (B) after autologous bone marrow (BM) or PBSC transplantation for AML in first CR by pretransplantation cytarabine consolidation therapy.

Multivariate Analyses 

In all multivariate analyses, the risk of transplantation outcomes was virtually identical for the standard- and high-dose cytarabine groups. Consequently, only the RR risks with consolidation versus without consolidation are presented here.

In multivariate analysis, TRM was higher among patients who received cytarabine alone for consolidation before autologous peripheral blood stem cell grafting. Among patients who received autologous bone marrow transplantation, TRM did not differ significantly between patients who did receive or did not receive pretransplantation consolidation (Table 4). The only factor associated with increased risk of TRM was French-American-British (FAB) classification. We found no statistically significant difference between pretransplantation consolidation therapy and purging, such that outcomes do not differ based on pretransplantation consolidation therapy and purging.

Table 4. Multivariate Analysis of Transplantation-Related Mortality in Patients Receiving Autologous Transplantation for AML in First CR

Variable⁎	n	Relative Risk (95% CI)	P Value
Pretransplantation consolidation therapy⁎
Bone marrow graft			P†overall = .24
No pretransplantation consolidation	117	1.00‡	P12 = .15
Standard or high-dose cytarabine alone	42	2.05(0.77-5.51)	P13 = .98
Standard or high-dose cytarabine + other§	243	0.98(0.48-2.05)	P23 = .10
Peripheral blood stem cell graft			P†overall = .005
No pretransplantation consolidation	25	1.00‡	P12 = .75
Standard or high-dose cytarabine alone	38	1.21(0.38-3.87)	P13 = .027
Standard or high-dose cytarabine + other§	154	0.29(0.10-0.87)	P23 = .003
Other significant covariates
FAB classification
M1, M2	240	1.00‡	P¶overall = .032
M3	54	0.41(0.09-1.76)	.23
M4	140	2.11(1.15-3.86)	.016
M5, M6, M7	141	1.15(0.56-2.36)	.71
Other/unclassified	44	2.13(0.90-5.09)	.09

CI indicates confidence interval; FAB, French-American-British classification.

After both bone marrow and peripheral blood stem cell grafting, the risk of relapse was lower in the patients who received cytarabine consolidation than in those who did not receive consolidation, although the effect of pretransplantation consolidation was greater in patients receiving peripheral blood stem cell grafts (Table 5) (P <.001).

Table 5. Multivariate Analysis of Relapse in Patients Receiving Autologous Transplantation for AML in First CR

Variables	n	Relative Risk (95% CI)	P Value
Pretransplantation consolidation therapy⁎
Bone marrow graft
No pretransplantation consolidation	117	1.00†
Standard or high-dose cytarabine	285	0.71 (0.51-1.00)	.051
Peripheral blood stem cell graft
No pretransplantation consolidation	25	1.00†
Standard or high-dose cytarabine	192	0.36 (0.21-0.63)	<.001

CI indicates confidence interval.

Previous consolidation was associated with a lower risk of treatment failure (relapse or death) with both graft types, but the effect was greater and the association stronger in those patients receiving peripheral blood stem cell grafting (Table 6; Figure 2A; P <.001). Other factors associated with LFS were FAB classification and time from diagnosis to first CR.

Table 6. Multivariate Analysis of Leukemia-free Survival in Patients Receiving Autologous Transplantation for AML in First CR

Variables	n	Relative Risk of Death or Relapse (95% CI)	P Value
Pretransplantation consolidation therapy
Bone marrow graft
No pretransplantation consolidation	117	1.00⁎
Standard or high-dose cytarabine	285	0.73(0.54-0.99)	.048
Peripheral blood stem cell graft
No pretransplantation consolidation	25	1.00⁎
Standard or high-dose cytarabine	192	0.40(0.25-0.65)	<.001
Other significant covariates
FAB classification
M1, M2	240	1.00⁎	P†overall = .031
M3	54	0.44(0.26-0.75)	.003
M4	140	1.12(0.84-1.50)	.45
M5, M6, M7	141	0.98(0.73-1.33)	.92
Other/unclassified	44	0.92(0.57-1.47)	.72
Time from diagnosis to CR1
≤2 months	447	1.00⁎	P‡overall = .041
>2 months	160	1.34(1.03-1.72)	.027
Missing	12	0.54(0.17-1.69)	.29

CI indicates confidence interval; FAB, French-American-British classification; CR, complete remission.

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• Figure 2. 

  Adjusted probabilities of LFS (A) and overall survival (B) after autologous bone marrow (BM) or PBSC transplantation for AML in first CR by cytarabine pretransplantation consolidation therapy.

Similarly, the risk of death was lower in patients who received standard-dose or high-dose cytarabine compared with those who did not receive pretransplantation consolidation (Table 7; Figure 2B). Other factors associated with survival were FAB classification and previous myelodysplastic syndrome.

Table 7. Multivariate Analysis of Survival in Patients Receiving Autologous Transplantation for AML in First CR

Variables⁎	n	Relative Risk of Death (95% CI)	P Value
Pretransplantation consolidation therapy⁎
Bone marrow graft
No pretransplantation consolidation	119	1.00†
Standard or high-dose cytarabine	290	0.70(0.51-0.97)	.031
Peripheral blood stem cell graft
No pretransplantation consolidation	25	1.00†
Standard or high-dose cytarabine	198	0.38(0.24-0.62)	<.001
Other significant covariates
FAB classification
M1, M2	249	1.00†	P‡overall=.012
M3	56	0.44(0.24-0.81)	.008
M4	142	1.30(0.96-1.76)	.10
M5, M6, M7	141	1.16(0.85-1.59)	.35
Other/unclassified	44	0.99(0.58-1.61)	.90
Previous myelodysplastic syndrome
No	609	1.00†
Yes	23	1.99(1.16-3.40)	.012

CI indicates confidence interval; FAB, French-American-British classification.

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Discussion 

Our study shows that consolidation with cytarabine before undergoing AuSCT for AML in first CR decreases the risks of relapse and treatment failure. This benefit was greatest in the recipients of peripheral blood stem cell autografts. Mehta et al. [19] reported conceptually similar results. In contrast, Cahn et al. [20] found no effect of the cytarabine dose used for consolidation on transplantation outcome; however, only 43 of the 841 patients in their study (5%) did not receive consolidation.

In the current study it was somewhat surprising, in view of the similarity in TRM and reportedly better antileukemia effects of higher doses of cytarabine in conventional AML therapy, that outcome did not differ between the standard-dose and high-dose cytarabine groups. It is possible that the high doses of chemotherapy given with autotransplantation produce similarly favorable outcomes in patients once a minimal residual leukemia state has been achieved with any dose of postremission chemotherapy. The reason for the apparent lack of a dose-response relationship is not clear; however, it may be that the high dose of chemotherapy administered with the transplantation overwhelms any dose effect of the pretransplantation consolidation. We also studied the effect of pretransplantation consolidation therapy according to age group (age ≤19 years vs >19 years) and found no statistically significant interaction between pretransplantation consolidation therapy and age (data not shown). Our results in autotransplantation recipients differ from our findings in allotransplantation recipients, in whom potent GVL effects add to the antileukemia effects of high-dose conditioning [14]. In the latter setting, previous consolidation therapy was not associated with posttransplantation outcome. In the absence of a GVL effect after autotransplantation, postremission consolidation chemotherapy before AuSCT appears to be important. Furthermore, with increasingly lower rates of TRM, the favorable impact of pretransplantation consolidation on leukemia recurrence may translate to a long-term survival benefit [21].

Several limitations of this study deserve comment. First, the decision to use postremission therapy was possibly not random. Patients at highest risk for leukemia relapse may have received postremission therapy more often than those believed to be not at high risk for relapse. However, this should have biased the outcome in favor of the no consolidation cohort. In fact, patients receiving no pretransplantation consolidation appear to be at higher risk, with trends (some statistically significant) toward more extramedullary disease, more previous myelodysplasia, and, importantly, a requirement for more cycles of chemotherapy to achieve CR. We examined these covariates in multivariate analyses and found that none was statistically significant. In addition, we repeated the analyses restricting the population to those patients achieving CR after 1 or 2 cycles of induction therapy and found that the RRs of all outcomes were virtually identical (data not shown). Unfortunately, a significant number of patients in both groups lacked cytogenetic data. Given the recent evidence that high-dose cytarabine may be particularly effective in core-binding factor leukemias, further analyses of outcome by subsets within cytogenetic risk groups would have been useful [22, 23]. We also did not find any statistically significant interaction between pretransplantation consolidation therapy and whether the patient had de novo or secondary AML.

Another limitation of the current study is that the patient groups were heterogeneous. There were other treatment differences among the cohorts. There may have been differences in anthracycline doses. Most (83%) patients in the no consolidation group received bone marrow treated in vitro to remove leukemia cells, which has been associated with a lower relapse risk than the use of blood cell grafts [24]. Again, this should have biased the outcome in favor of the no consolidation cohort.

A third study limitation was the longer interval from remission to autotransplantation in the patients in the consolidation groups, which may have introduced lead-time bias. That is, the longer interval from first CR to graft harvest and autotransplantation may have led to the exclusion of patients who relapsed early after induction. We tried to explore this issue in 2 ways. First, we considered time from first CR to transplantation and from diagnosis to transplantation as covariates in the Cox regression models. We found that neither of these covariates was statistically significant, and also that including them did not affect the association between consolidation and outcome. Second, we repeated the analyses restricting the population to patients undergoing transplantation within 4 months of achieving CR. Although this greatly decreased the size of the consolidation group, the RRs of transplantation outcomes were similar. The RR of treatment failure for standard or high-dose cytarabine versus no pretransplantation consolidation was 0.90 (95% confidence interval [CI] = 0.63-1.30) (P = .58) for bone marrow grafting and 0.40 (95% CI = 0.23-0.72) (P = .002) for peripheral blood stem cell (PBSC) grafting. The RR of overall mortality for standard or high-dose cytarabine versus no pretransplantation consolidation was 0.79 (95% CI = 0.54-1.16) (P = .23) for bone marrow grafting and 0.35 (95% CI = 0.19-0.62) (P = < .001) for PBSC grafting.

A fourth limitation is that the patients receiving high-dose cytarabine consolidation were treated more recently, and it is possible that their improved outcome compared with that of the no consolidation group was influenced in part by advances in supportive care and more frequent use of PBSCs as the source of hematopoietic reconstitution. Finally, the conclusions drawn here apply only to patients who remain in first CR sufficiently long to receive autotransplantation; it is not an intention-to-treat analysis. For these reasons, it is important that the results of this study be confirmed in a randomized clinical trial. The data provided here will be important to consider in planning such a trial. In addition, this study does not establish the optimal dose or schedule of cytarabine to administer before autotransplantation. Although most patients received 1 or 2 cycles of consolidation, the number of courses administered had no detectable effect on transplantation outcome.

Despite the absence of postremission therapy in 1 cohort, the 5-year LFS was 40%. Furthermore, the lack of a major difference in LFS among patients receiving standard-dose and high-dose cytarabine and the relapse rate of 35%-40% suggests that future efforts might be focused on novel posttransplantation strategies to prevent relapse rather than on simply more intensive pretransplantation or posttransplantation chemotherapy.

Although this study demonstrates a benefit of intensive consolidation before autologous transplantation for AML in first CR, historically randomized trials have not shown a benefit of autologous transplantation compared with intensive consolidation chemotherapy. This may be due in part be due to the relatively high early TRM rate at the time that these trials were conducted (approximately 15% vs 10% in the current study), which may have muted the potential benefit in outcome. The results presented herein suggest that patients undergoing AuSCT for AML in first CR may benefit from additional postremission chemotherapy before high-dose therapy, with reduced relapse and treatment failure. This effect is particularly apparent among patients receiving stem cells procured from the peripheral blood rather than from the bone marrow. We found no advantage of high-dose cytarabine over standard-dose cytarabine. Thus, patients may reasonably receive consolidation with either standard or high-dose cytarabine, based on local institutional standards, before AuSCT for AML in first CR, although prospective studies evaluating the role of postremission therapy and optimal schedules and doses are still needed.

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Acknowledgments 

This work was supported by Public Health Service Grant U24-CA76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute; the Office of Naval Research; the Health Resources Services Administration (DHHS); AABB, Aetna; AIG Medical Excess; American Red Cross; Amgen; Inc.; an anonymous donation to the Medical College of Wisconsin; AnorMED, Inc.; Berlex Laboratories, Inc.; Biogen IDEC, Inc.; Blue Cross and Blue Shield Association; BRT Laboratories, Inc.; Celgene Corp.; Cell Therapeutics, Inc.; CelMed Biosciences; Cubist Pharmaceuticals; Dynal Biotech, LLC; Edwards Lifesciences RMI; Endo Pharmaceuticals, Inc.; Enzon Pharmaceuticals, Inc.; ESP Pharma; Fujisawa Healthcare, Inc.; Gambro BCT, Inc.; Genzyme Corporation; GlaxoSmithKline, Inc.; Histogenetics, Inc.; Human Genome Sciences; ILEX Oncology, Inc.; Kirin Brewery Company; Ligand Pharmaceuticals, Inc.; Merck & Company; Millennium Pharmaceuticals; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec; National Center for Biotechnology Information; National Leukemia Research Association; National Marrow Donor Program; NeoRx Corporation; Novartis Pharmaceuticals, Inc.; Novo Nordisk Pharmaceuticals; Ortho Biotech, Inc.; Osiris Therapeutics, Inc.; Pall Medical; Pfizer, Inc.; Pharmion Corp.; QOL Medical; Roche Laboratories; StemCyte, Inc.; Stemco Biomedical; StemSoft Software, Inc.; SuperGen, Inc.; Sysmex; The Marrow Foundation; THERAKOS, a Johnson & Johnson company; University of Colorado Cord Blood Bank; Valeant Pharmaceuticals; ViaCell, Inc.; ViraCor Laboratories; W.B. Saunders, Mosby, Churchill Livingstone; and Wellpoint Health Network. The contents of this article are the responsibility of the authors and do not represent the official views of the National Cancer Institute.

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