Impact of postremission consolidation chemotherapy on outcome after reduced-intensity conditioning allogeneic stem cell transplantation for patients with acute myeloid leukemia in first complete remission: A report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Authors


  • We would like to thank all the participating European Group for Blood and Marrow Transplantation centers, physicians, and local data managers. Special thanks to Leila Moukhtari, Emmanuelle Polge, and Hervé Finel for their excellent data collection and management.

Abstract

BACKGROUND

The objective of the current study was to investigate the role of postremission consolidation chemotherapy before reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (alloSCT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1).

METHODS

Of the 789 consecutive patients with AML in CR1 who underwent RIC alloSCT from a human leukocyte antigen-matched sibling or matched unrelated donor peripheral stem cell grafts between 2001 and 2010, 591 patients received at least 1 cycle of consolidation chemotherapy and 198 patients did not receive any consolidation chemotherapy before alloSCT. To minimize inherent survival bias in favor of patients who underwent transplant long after achieving CR1, the study focused on 373 patients who underwent transplant within the median time frame between achievement of CR1 and alloSCT (3 months for patients who underwent alloSCT from matched siblings and 4 months for patients who underwent alloSCT from matched unrelated donors). In this subgroup, 151 patients did not receive any consolidation chemotherapy and 222 patients received ≥ 1 consolidation chemotherapy cycle.

RESULTS

With a median follow-up of 36 months (range, 2 months-135 months), the 3-year cumulative recurrence incidence (RI) was not significantly different between the groups (36% ± 4% for the group treated without consolidation chemotherapy vs 38% ± 3% for patients who received consolidation chemotherapy; P = .89). In addition, leukemia-free survival was similar between the groups (45% ± 4% and 47% ± 3%, respectively; P = .41). Dose intensity of cytarabine given during consolidation chemotherapy appeared to have no influence on RI. On multivariate analysis, pretransplant consolidation (≥ 1 cycle vs 0 cycles) was found to have no significant impact on RI (hazards ratio, 1.29; 95% confidence interval, 0.84-1.97 [P = .24]) or leukemia-free survival (hazards ratio, 1.00; 95% confidence interval, 0.71-1.42 [P = .99]).

CONCLUSIONS

The data from the current study suggest no apparent advantage for postremission consolidation chemotherapy before RIC alloSCT, provided a donor is readily available. Cancer 2014;120:855–863. © 2013 American Cancer Society.

INTRODUCTION

The role of consolidation chemotherapy after successful remission induction is well established in the treatment paradigm of patients with acute myeloid leukemia (AML) in first complete remission (CR1) in the nontransplant setting.[1-3] Consolidation chemotherapy courses have been proven to decrease leukemia recurrence and improve survival. Thus, most contemporary treatment protocols for young patients with AML in CR1 who are not undergoing transplantation include repetitive cycles of high-dose cytarabine.[1-4] Allogeneic stem cell transplantation (alloSCT) is a potentially curative therapy for patients with AML that likely provides the most potent antileukemic effect of any postremission strategy.[5] Nevertheless, whether there is a need for postremission consolidation chemotherapy before alloSCT is an unresolved issue. In the standard myeloablative conditioning (MAC) alloSCT setting, pretransplant consolidation chemotherapy did not prove to have a significant beneficial impact on the overall survival (OS), leukemia-free survival (LFS), or recurrence incidence (RI) of patients with AML in CR1, as suggested by 2 large retrospective registry analyses from the International Bone Marrow Transplant Registry (IBMTR) and the European Group for Blood and Marrow Transplantation (EBMT).[6, 7] Thus, for a patient with AML in CR1 who is a candidate for alloSCT with MAC, there may be no need for consolidation chemotherapy before proceeding to transplantation. Nevertheless, this conclusion may not be applicable to the reduced-intensity conditioning (RIC) alloSCT setting, which relies mainly on the immunologic graft-versus-leukemia (GVL) effect rather than on the antileukemic potency of the preparative regimen.[8-11] Given the possible increased risk of AML recurrence after RIC alloSCT, one may hypothesize that an improved reduction of leukemic burden by consolidation chemotherapy before transplantation is mandatory if one wants to reduce the posttransplant RI and thereby improve transplantation outcome. However, to the best of our knowledge, the value of consolidation chemotherapy before RIC alloSCT in patients with AML in CR1 has not yet been investigated. In addition, the optimal number of consolidation chemotherapy cycles that should be given before RIC alloSCT and the questionable advantage of higher versus lower doses of cytarabine-based consolidation are also issues of concern. Nonetheless, one must also acknowledge that the toxicity resulting from unnecessary consolidation chemotherapy may preclude subsequent alloSCT or increase transplant-related morbidity and mortality. Thus, the objective of the current multicenter retrospective analysis was to assess the role of pretransplant consolidation chemotherapy before RIC alloSCT in a large cohort of patients with AML in CR1 who received human leukocyte antigen (HLA)-identical sibling or matched unrelated donor (MUD) peripheral blood stem cell (PBSC) grafts.

MATERIALS AND METHODS

Inclusion Criteria and Data Collection

The current study was a retrospective study performed by the Acute Leukemia Working Party (ALWP) of the EBMT. The scientific board of the ALWP approved the study. Patients with AML were selected from the registry according to the following criteria: 1) age ≥ 18 years at the time of transplantation; 2) in CR1; 3) requiring only 1 or 2 cycles of induction to achieve CR1; 4) receiving their first SCT; 5) matched sibling or MUD transplant was used; 6) RIC was used; 7) unmanipulated PBSC grafts were used; and 8) patients underwent transplant between 2001 and 2010. Demographic data, details regarding transplantation, and posttransplantation updates were extracted from the EBMT database. Furthermore, for the purpose of the current study, additional data were requested from investigators and collected. Transplant centers received a specifically designed questionnaire that asked for details concerning characteristics of induction and postremission consolidation chemotherapy, including the number of induction cycles (including drug composition and exact dosages) and the number of consolidation cycles (including drug composition and exact dosages).

Definitions

Cytogenetic subgroups were defined as previously described.[12] The number of induction cycles (1 cycle vs 2 cycles) was defined according to the number of induction cycles needed to achieve CR1. Among patients who achieved CR1 after 1 cycle of induction chemotherapy but who received a second induction cycle as per protocol, the second cycle was considered to a consolidation cycle as part of the current analysis. The dose intensity of cytarabine was defined as follows: standard dose, 100 to 200 mg/m2 per dose; high-dose, ≥ 1 g/m2 per dose; and intermediate dose, a dose falling between the standard dose and high-dose regimens.[6, 13]

According to EBMT criteria, RIC was defined as 1) oral busulfan at a dose of < 8 mg/kg or intravenous busulfan at a dose of < 6.4 mg/kg with or without total body irradiation (TBI) ≤ 6 gray (Gy) (fractionated) with or without purine analog with or without antithymocyte globulin (ATG); 2) cyclophosphamide at a dose of 60 mg/kg with or without TBI ≤ 6 Gy (fractionated) with or without purine analog with or without ATG; 3) melphalan at a dose of 140 mg/m2 plus fludarabine with or without ATG; and 4) TBI ≤ 6 Gy (fractionated) with or without purine analog with or without ATG.[14]

Statistical Analysis

Patient-related and disease-related variables of the 2 groups (those who received consolidation chemotherapy vs those who did not) were compared using the chi-square test for categorical variables and the Mann-Whitney U test for continuous variables. Variables considered were patient age at time of transplantation, cytogenetic risk group, number of induction cycles to achieve CR1, interval from CR1 to transplantation, type of donor, conditioning regimen (TBI vs chemotherapy alone), and the use of ATG. LFS was defined as survival without evidence of disease recurrence or progression. Nonrecurrence mortality (NRM) was defined as death while the patient was in CR. Cumulative incidence curves were used for RI and NRM in a competing risk setting because death and disease recurrence are competing together and the Gray test was used for univariate comparisons.[15] Probabilities of OS and LFS were calculated using the Kaplan-Meier estimates. The log-rank test was used for univariate comparisons. All factors studied were included in the Cox proportional hazards model.[16] Interactions between the use of consolidation chemotherapy, interval from CR1 to transplantation, and each other factor were systematically tested. The interval from CR to transplant was included in the Cox model as a continuous variable. Proportional hazards assumptions were checked systematically using the Grambsch-Therneau residual-based test.[17] All tests were 2-sided. The type I error rate was fixed at 0.05 for the determination of factors associated with time-to-event outcomes. Statistical analyses were performed with SPSS (version 19; SPSS Inc, Chicago, Ill) and R (version 2.13.2; R Development Core Team, Vienna, Austria) statistical software packages.

RESULTS

Overall Outcome

From January 2001 to December 2010, 2560 patients with AML in CR1 had undergone an alloSCT after a RIC regimen and were registered in the ALWP of the EBMT database. Extensive data (Med A and B and a specifically designed questionnaire) regarding 1125 patients (44%) were provided by 75 participating centers (32%). A total of 789 of these 1125 patients (70%) met the inclusion criteria. In the current study cohort, 591 patients received at least 1 course of consolidation chemotherapy before alloSCT and 198 patients did not.

With a median follow-up of 40 months from transplantation (range, 1 month-140 months), the Kaplan-Meier estimates of OS and LFS at 3 years were 55% (95% confidence interval [95% CI], 52%-59%) and 52% (95% CI, 48%-55%), respectively. The cumulative incidence of disease recurrence was 33% (95% CI, 29%-36%) and the cumulative incidence of NRM was 15% (95% CI, 13%-18%).

The median time between achievement of CR1 and undergoing alloSCT was 3 months for patients who received transplants from a sibling donor (range, 0.3 months-15 months) and 4 months for patients who received MUD transplants (range, 0.2 months-12 months) (P = .001). The median time from CR1 to alloSCT was found to be longer among patients who received consolidation chemotherapy compared with those who received no consolidation chemotherapy (4.7 months vs 2.2 months; P < .001). Among patients who underwent transplant within the median time between CR1 and alloSCT, 40% did not receive any consolidation chemotherapy (151 of 373 patients), whereas among those patients who underwent transplant beyond the median time, only 11% did not receive any consolidation chemotherapy (47 of 416 patients) (P < .001).

It is interesting to note that among patients who received pretransplant consolidation chemotherapy (n = 591), those who underwent transplant beyond the median time frame between CR and transplantation (n = 369) had an improved 3-year LFS compared with patients who underwent transplant within the median time frame (n = 222) (58% [95% CI, 53%-64%] vs 47% [95% CI, 41%-54%], respectively; P = .002). Although NRM was not found to be significantly different between the 2 groups (14% [95% CI, 10%-18%] vs 14% [95% CI, 10%-20%]; P = .43), this was solely due to a lower RI in patients who underwent transplant beyond the median time frame (28% [95% CI, 23%-33%] vs 38% [95% CI, 31%-44%], respectively; P = .009), which was irrespective of the number of consolidation cycles actually delivered (1 cycle vs > 1 cycle), thus reflecting a selection bias in favor of patients surviving longer without disease recurrence occurring before transplantation.

Outcome of Patients Who Underwent Transplant Within the Median Time Frame Between CR and alloSCT

Based on the above findings, and to minimize the inherent survival bias in favor of patients who underwent transplant long after achieving CR1, we elected to focus on the group of 373 patients who underwent transplant within the median time frame between CR1 and alloSCT (3 months for patients receiving a matched sibling transplant and 4 months for patients receiving a MUD transplant) (Table 1). In this subgroup, 151 patients did not receive any consolidation chemotherapy and 222 patients received ≥ 1 consolidation chemotherapy cycle (164 patients received 1 cycle and 58 patients received ≥ 2 cycles). Patients treated without consolidation chemotherapy were older (median age, 58 years vs 56 years; P = .03), had a shorter time from CR1 to alloSCT (56 days vs 71 days; P < .001), more often required 2 inductions to achieve CR1 (80% vs 35%; P < 0.001), more often received TBI-based conditioning (57% vs 23%; P < .001), and less frequently received ATG (29% vs 42%; P = .008). Factors such as year of alloSCT, patient sex, cytogenetic risk group, donor type (MUD vs sibling), and female donor-to-male recipient sex combination were not found to be significantly different between the 2 groups. With a median follow-up of 36 months (range, 2 months-135 months), the 3-year cumulative incidence of disease recurrence was not found to be significantly different between the 2 groups (36% [95% CI, 28%-44%] for patients with no consolidation chemotherapy and 38% [95% CI, 31%-45%] for patients who received consolidation chemotherapy; P = .89). In addition, LFS was similar between the groups (45% [95% CI, 36%-53%] vs 47% [95% CI, 41%-54%], respectively; P = .41) (Table 2). It is interesting to note that the dose intensity of cytarabine given during consolidation chemotherapy and the number of consolidation cycles was found to have no impact on RI and LFS.

Table 1. Patient-, Disease-, and Treatment-Related Characteristics of Patients Who Underwent Transplant Within the Median Time Frame Between Achievement of CR and alloSCT
Variable No Consolidation Chemotherapy Cycles

N = 151

1 or More Consolidation Chemotherapy Cycles

N = 222

P
  1. Abbreviations: alloSCT, allogeneic stem cell transplantation; ATG, antithymocyte globulin; CR, complete remission; CR1, first CR; GVHD, graft-versus-host disease; MUD, matched unrelated donor; TBI, total body irradiation.

Median age (range), y 58 (30-76)56 (19-70).03
Cytogenetic risk groupGood4 (3%)8 (4%).4
Intermediate102 (68%)162 (73%)
Poor28 (19%)37 (17%)
Missing data17 (11%)15 (7%)
No. of induction cycles before CR1130 (20%)144 (65%)<0.001
2121 (80%)78 (35%)
Interval from CR1 to alloSCT (range), d 56 (11-119)71 (10-121)<0.001
Y of transplantation (range) 20082008.11
 (2001-2010)(2001-2010)
Donor typeSibling111 (74%)152 (68%).3
MUD40 (26%)70 (32%)
Patient sexMale75 (50%)116 (52%).62
Female76 (50%)106 (48%)
Donor sexMale91 (60%)128 (58%).62
Female60 (40%)94 (42%)
Female-to-male sex combinationNo126 (83%)184 (83%).89
Yes25 (17%)38 (17%)
TBI-based conditioning regimenNo65 (43%)172 (77%)<0.001
Yes86 (57%)50 (23%)
ATG for GVHD preventionNo108 (71%)129 (58%).008
Yes43 (29%)93 (42%)
Table 2. Univariate Analysis for Transplant Outcomes Among Patients Who Underwent Transplant Within the Median Time Frame Between Achievement of CR and alloSCT
 3-Year Results (No.)LFS (95% CI), %OS (95% CI), %RI (95% CI), %NRM (95% CI), %
  1. Abbreviations: 95% CI, 95% confidence interval; alloSCT, allogeneic stem cell transplantation; ATG, antithymocyte globulin; CR, complete remission; CR1, first CR; GVHD, graft-versus-host disease; LFS, leukemia-free survival; MSD, matched sibling donor; MUD, matched unrelated donor; NRM, nonrecurrence mortality; OS, overall survival; RI, recurrence incidence; TBI, total body irradiation.

CytogeneticsPoor (n = 65)36 (22-49)36 (22-49)46 (33-59)18 (9-30)
 Other (n = 308)48 (42-54)52 (46-58)36 (30-41)16 (12-20)
P .07.08.07.83
No. of induction cycles1 (n = 174)47 (39-55)49 (41-57)35 (27-42)18 (12-24)
 2 (n = 199)46 (38-53)50 (43-57)40 (32-46)15 (10-20)
P .9.58.5.31
Consolidation     
 Yes (n = 222)47 (41-54)51 (43-59)38 (31-45)14 (10-18)
 No (n = 151)45 (36-53)48 (40-56)36 (28-44)19 (13-25)
P .41.48.89.24
No. of consolidations1 (n = 164)45 (37-53)49 (41-57)38 (31-46)17 (12-23)
 >1 (n = 58)56 (43-69)57 (44-71)37 (24-50)7 (2-16)
P .23.19.91.05
High-dose cytarabine at consolidation     
 No (n = 84)55 (44-66)55(43-66)33 (23-43)12 (6-21)
 Yes (n = 138)44 (35-52)49 (40-58)41 (32-49)15 (10-22)
P .57.68.72.77
Interval from CR1 to alloSCT     
 <Median (n = 189)47 (39-54)50 (43-58)36 (29-43)17 (12-23)
 > Median (n = 184)46 (38-53)49 (41-57)39 (32-46)15 (10-21)
P .99.87.66.65
Age at transplantation     
Median, 57 y<Median (n = 187)50 (42-57)54 (46-61)37 (30-45)12 (8-18)
 >Median (n = 186)42 (35-50)45 (38-53)32 (30-45)20 (14-26)
P .45.66.73.16
Y of transplantation<Median (n = 187)45 (38-52)50 (42-57)39 (32-46)16 (11-22)
 >Median (n = 186)48 (40-56)51 (42-59)35 (27-42)17 (11-23)
P .7.84.91.9
Donor typeMSD (n = 263)48 (42-54)51 (45-58)36 (30-42)16 (12-21)
 MUD (n = 110)42 (32-53)45 (35-56)40 (31-50)17 (10-26)
P .49.52.42.82
Patient sex     
 Male (n = 191)43 (36-50)46 (39-54)39 (32-46)18 (12-24)
 Female (n = 182)50 (42-58)53 (45-61)35 (28-43)15 (10-20)
P .07.11.24.41
Donor sexMale (n = 219)45 (38-52)49 (42-56)41 (34-48)14 (9-19)
 Female (n = 154)48 (40-56)51 (42-59)32 (25-40)20 (14-26)
P .45.66.1.23
Female donor to male recipient     
 No (n = 310)46 (40-52)49 (43-55)38 (33-44)15 (12-20)
 Yes (n = 63)48 (35-60)51 (38-64)33 (21-45)19 (11-30)
P .53.48.36.65
TBI-based conditioning regimen     
 No (n = 237)50 (44-57)52 (45-59)33 (27-36)17 (12-22)
 Yes (n = 136)40 (31-49)46 (37-55)45 (36-53)16 (10-23)
P .16.35.04.44
ATG for GVHD prophylaxis     
 No (n = 237)44 (37-51)47 (40-54)38 (31-44)18 (13-23)
 Yes (n = 136)51 (42-60)54 (45-53)36 (27-44)14 (8-21)
P .19.19.55.32

To further minimize the potential selection bias that would favor those patients who did not develop disease recurrence before transplantation despite not receiving any consolidation chemotherapy, we compared the subgroup of patients without consolidation chemotherapy who merely underwent transplant within 2 months from CR (n = 74) with the group of patients receiving consolidation chemotherapy and who underwent transplant within the median time frame between CR1 and alloSCT (n = 222; 3 months for patients with sibling donors and 4 months for patients with MUDs), and the outcomes were still comparable (P = .89).

On multivariate analysis adjusting for patient age, cytogenetic risk group, number of induction cycles, time from CR to transplantation, donor type, conditioning regimen category, and use of ATG, delivering pretransplant consolidation chemotherapy (≥ 1 cycle vs 0 cycles) appeared to have no significant impact on RI (hazard ratio [HR], 1.29; 95% CI, 0.84-1.97 [P = .24]) or LFS (HR, 1.00; 95% CI, 0.71-1.42 [P = .99]) (Table 3). Nevertheless, on multivariate analysis adjusting for the same variables, there was a trend toward higher NRM in patients who underwent transplant without consolidation chemotherapy (HR, 0.59; 95% CI, 0.32-1.09 [P = .09]).

Table 3. Multivariate Analysis for Transplant Outcomes of Patients Who Underwent Transplant Within the Median Time Frame Between Achievement of CR and alloSCT
 VariableHR95% CIP
  1. Abbreviations: 95% CI, 95% confidence interval; alloSCT, allogeneic stem cell transplantation; ATG, antithymocyte globulin; CR, complete remission; CR1, first CR; HR, hazards ratio; LFS, leukemia-free survival; MUD, matched unrelated donor; NRM, nonrecurrence mortality; OS, overall survival; RI, recurrence incidence; TBI, total body irradiation; Tx, transplantation.

RIConsolidation vs no consolidation1.290.84-1.97.24
 Age >median0.990.71-1.38.95
 No. of induction cycles1.120.76-1.64.58
 Interval from CR1 to Tx0.990.98-1.00.01
 MUD vs sibling donor1.380.91-2.1.13
 Poor cytogenetics6.652.76-16<.0001
 TBI1.390.95-2.03.09
 ATG0.780.51-1.18.24
 Interaction between poor karyotype and interval from CR1 to Tx0.980.96-0.99.001
NRMConsolidation vs no consolidation0.590.32-1.09.09
 Age >median1.350.82-2.22.24
 No. of induction cycles0.650.36-1.18.16
 Interval from CR1 to Tx1.000.99-1.02.70
 MUD vs sibling donor1.090.57-2.1.79
 Poor cytogenetics0.620.1-3.75.60
 TBI0.780.44-1.39.40
 ATG0.700.38-1.30.26
 Interaction between poor karyotype and interval from CR1 to Tx1.010.99-1.03.45
LFSConsolidation vs no consolidation1.000.71-1.42.99
 Age >median1.090.82-1.43.56
 No. of induction cycles0.940.68-1.3.72
 Interval from CR1 to Tx0.990.99-1.03
 MUD vs sibling donor1.330.94-1.89.11
 Poor cytogenetics3.601.67-7.74.001
 TBI1.150.84-1.58.39
 ATG0.750.53-1.06.11
 Interaction between poor karyotype and interval from CR1 to Tx0.990.97-1.01
OSConsolidation vs no consolidation0.960.66-1.39.82
 Age >median1.220.92-1.63.18
 No. of induction cycles0.880.63-1.24.47
 Interval from CR1 to Tx0.990.99-1.15
 MUD vs sibling donor1.290.89-1.87.18
 Poor cytogenetics3.321.47-7.5.004
 TBI1.070.77-1.49.69
 ATG0.740.52-1.07.11
 Interaction between poor karyotype and interval from CR1 to Tx0.990.97-1.03

We found an interaction between cytogenetic risk group and the interval from CR1 to alloSCT; the impact of cytogenetics was essentially found in patients who underwent transplant early after achieving CR. Taking this interaction into account, poor cytogenetics was associated with higher rates of disease recurrence (HR, 6.65; 95% CI, 2.76-16 [P < .0001]), lower LFS (HR, 3.6; 95% CI, 1.67-7.74 [P = .001]), and lower OS (HR, 3.32; 95% CI, 1.47-7.5 [P = .004]). A longer interval from CR1 to transplantation was associated with lower rates of disease recurrence (HR, 0.99; 95% CI, 0.98-1 [P = .01]) and better LFS (HR, 0.99; 95% CI, 0.99-1 [P = .03]).

Outcome of Patients Who Underwent Transplant Beyond the Median Time Frame Between CR1 and alloSCT

In the subgroup of patients who underwent transplant beyond the median time frame between CR1 and alloSCT, only 47 patients did not receive any consolidation chemotherapy whereas 369 patients received ≥ 1 consolidation chemotherapy cycle (170 patients received 1 cycle and 199 patients received ≥ 2 cycles). With a median follow-up of 43 months (range, 1 month-140 months), the 3-year LFS rate was significantly lower for patients with no consolidation chemotherapy compared with patients with consolidation chemotherapy (43% [95% CI, 28%-57%] vs 58% [95% CI, 53%-64%], respectively; P = .03). Although the RI was not found to be significantly different between the groups (33% [95% CI, 20%-47%] vs 28% [95% CI, 23%-33%]; P = .38), these results were solely attributed to an increased NRM rate among patients treated without consolidation chemotherapy (24% [95% CI, 13%-37%] vs 14% [95% CI, 10%-18%]; P = .09), most likely reflecting a selection bias in favor of patients who were able to tolerate ≥ 1 consolidation chemotherapy cycles versus patients remaining without consolidation chemotherapy for a prolonged period of time.

DISCUSSION

The purpose of the current retrospective study was to address a frequently encountered dilemma regarding whether there is a need for postremission consolidation chemotherapy in patients with AML in CR1 who are candidates for RIC alloSCT, provided a suitable donor is readily available. As has previously been shown in the standard MAC setting,[6, 7] the results of the current study suggest that pretransplant consolidation chemotherapy has no beneficial impact on the outcome of patients with AML in CR1 who are receiving RIC alloSCT, because patients with and without consolidation chemotherapy in the current study had similar RI, LFS, and OS. Such comparable results were observed despite the finding that patients who did not receive any consolidation chemotherapy were older (58 years vs 56 years; P = .03), more often required 2 cycles of induction chemotherapy to achieve CR1 (80% vs 35%; P < .001), and had a shorter interval from CR1 to transplantation (56 days vs 71 days; P < 0.001). The most likely explanation for the similar RI, LFS, and OS outcomes noted among patients with and without pretransplant consolidation chemotherapy is the strength of the GVL effect provided by alloSCT, which may overcome differences in the pretransplant leukemic cell burden.

One may challenge our method of distinguishing between true induction failure and thus the existence of a real need for a second induction cycle to obtain CR versus a decision based merely on the finding of increased blast cells in a bone marrow specimen that is hypocellular on day 14 after the initiation of therapy, which has been proven to be an error in predicting that it reflects residual leukemia.[18] Thus, some would venture that many patients received a second cycle of induction chemotherapy that was actually a form of consolidation, rather than a true second induction. However, according to a survey conducted by the ALWP, although the exact timing may vary among protocols, response assessment after induction chemotherapy is usually performed between 21 days and 28 days after the initiation of therapy or at the time of peripheral blood recovery. If at that point the bone marrow is hypoplastic, a repeat sample is obtained a week later. Thus, the decision regarding whether to administer a second induction cycle truly reflects residual leukemia, and thus the latter course should not be considered another form of consolidation chemotherapy.

The current study data indicating a trend toward higher NRM in patients who underwent transplant without consolidation chemotherapy (HR, 0.59; 95% CI, 0.32-1.09 [P = .09]) are not surprising given that the majority of these patients received 2 consecutive, intense, induction cycles, thus exposing them to added toxicity before transplantation. Moreover, the decision to go directly to RIC alloSCT without any consolidation chemotherapy is not the standard of care and most likely indicates a subgroup of patients with comorbidities.

An important pitfall that we had to overcome during the current analysis was the inherent survival bias in favor of patients who underwent transplant long after achieving CR1, which could have skewed our conclusions. Indeed, it could be demonstrated that among patients who received pretransplant consolidation chemotherapy, those who underwent transplant beyond the median time frame between CR1 and transplantation had a lower RI compared with those who underwent transplant within the median time frame (28% vs 38%; P = .009). The latter result was irrespective of the number of consolidation chemotherapies patients actually received (1 vs > 1), thus reflecting a selection bias in favor of patients surviving longer without disease recurrence before transplantation (because patients with early disease recurrence would have been excluded from the current analysis, which considered only patients in CR1). Thus, to minimize this inherent survival bias, we stratified patients according to time from CR1 to transplantation and focused on the subgroup of patients who underwent transplant within the median time frame between CR1 and RIC alloSCT. Indeed, in this subgroup, we observed that patients treated with or without pretransplant consolidation chemotherapy had comparable RI, LFS, and OS. It is interesting to note that in the subgroup of patients who actually received consolidation chemotherapy within the median time frame between CR1 and alloSCT, neither cytarabine dose intensity nor the number of consolidation cycles was found to have an impact on RI, further supporting our findings that there is no apparent advantage for pretransplant consolidation chemotherapy in the setting of RIC alloSCT.

As previously shown,[19] patients with poor cytogenetics had increased RI and decreased LFS. However, this impact was restricted to patients who underwent transplant early rather than later after achieving a CR, again reflecting a potential selection bias in favor of patients surviving longer without disease recurrence before transplantation.

Recently, several studies have demonstrated that minimal residual disease (MRD) that is detectable by flow cytometry at the time of MAC or RIC alloSCT was independently associated with increased RI and a shorter disease-free survival and OS.[20, 21] Because we did not collect data regarding pretransplant MRD status, it is unknown whether the lack of a benefit of postremission consolidation chemotherapy extends equally to MRD-negative and MRD-positive patients. Thus, future studies should address the issue of whether postremission consolidation chemotherapy could transform an MRD-positive state into an MRD-negative one, and whether the achievement of such negativity before alloSCT improves the outcome in these patients.

In the current study, only patients who underwent transplant with PBSC grafts were included. Recently, Nagler et al compared outcomes of PBSCs versus the bone marrow as the stem cell source for MUD RIC alloSCT in patients with AML in CR.[22] The RI at 2 years was significantly higher among patients who underwent transplant with bone marrow grafts compared with those who underwent transplant with PBSC grafts (46% vs 32%; P = .014). These results were suggestive of a stronger GVL effect with PBSC grafts, which are known to contain 20-fold more effector T cells compared with bone marrow grafts.[23, 24] Thus, whether the results of the current study are applicable to patients who underwent transplant with bone marrow grafts remains an open question.

The current study has several limitations. First, there was a lack of information regarding patients who were precluded from transplantation because of early disease recurrence or due to toxicities and mortality from consolidation chemotherapy. Furthermore, we lacked data regarding the reasons why patients were assigned their specific treatment. Importantly, one should bear in mind that the findings of the current study may not be applicable to patients with AML in CR1 who are candidates for RIC alloSCT but for whom a suitable donor is not immediately available. Such patients may still need to receive “bridging” consolidation chemotherapy while waiting for a donor to be identified in an attempt to decrease the risk of early disease recurrence before transplantation. The issue of the optimal dose of cytarabine in this setting also needs to be determined.

In conclusion, the results of the current study clearly suggest that, provided a suitable donor is readily available, there is no significant benefit to adding consolidation chemotherapy before RIC alloSCT, and that transplantation should be offered promptly at the time CR1 is achieved without undue delay. Nevertheless, further studies are warranted to confirm these results.

FUNDING SUPPORT

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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