Through two consecutive trials, a policy that considered allogeneic stem cell transplantation (SCT) from a sibling donor in second rather than first complete remission (CR) in selected younger patients with acute myeloid leukemia (AML) with t(8;21)/inv(16) (core binding factor (CBF) group) or a normal karyotype (NN group) was followed by Acute Leukemia French Association (ALFA) centers. The outcome of 92 of these patients in first relapse (32 CBF, 60 NN) was reviewed with the aim of validating this strategy. The presence of an FLT3 internal tandem duplication (ITD) was retrospectively assessed in 50 patients. A total of 61 patients (66%) reached a second CR. Donor availability was an independent prognostic factor for survival in the whole patient population as well as in the CBF subset, but not in NN patients, further supporting this strategy for CBF-AMLs. In NN patients, FLT3-ITD was the main bad-prognosis factor for second CR achievement and survival, leading to consider SCT earlier, at least in FLT3-ITD patients with a donor.
Allogeneic hematopoietic stem cell transplantation (SCT) from an HLA-matched sibling has been considered for years as the best treatment option to prevent relapse in younger adults with acute myeloid leukemia (AML) in first complete remission (CR). Following SCT, the risk of further relapse is generally less than 30% and lower than after conventional chemotherapy.1, 2, 3, 4 This benefit is, however, partially offset by the toxicity associated with the transplant procedure with treatment-related mortality (TRM) rates of 15–20%. Owing to increasing TRM with advanced age, conventional myeloablative SCT is usually restricted to patients under 50 years of age.
To avoid statistical bias, recent studies evaluating the role of SCT in first CR have been based on donor vs no-donor comparisons according to the results of HLA typing as a random allocation.5, 6, 7, 8, 9 Patients in first CR with suitable sibling donors have been compared with those without sibling donors. The use of more intensive regimens of chemotherapy has improved the outcome in the no-donor group enough so that no significant benefit in overall survival may be observed for the donor group. The importance of diagnostic cytogenetics as prognostic factor for outcome in patients with AML led investigators to compare SCT and chemotherapy within each cytogenetic subgroup. Results show that SCT in first CR does not appear to benefit to relatively good-risk AML patients, as those with t(8,21), inv(16/t(16;16) or a normal karyotype (NN group).8, 9 The French AML Intergroup has recently reported the results of two large retrospective studies conducted in patients with t(8;21) and inv(16) AML, which both confirm this observation in patients with core binding factor (CBF) AML.10, 11 No controlled study has, however, formally compared SCT in second vs first CR in selected AML patients. There is consequently no consensus on the appropriate group of patients in whom SCT might be safely delayed in second CR.
As a common multicenter prospective policy to delay SCT in second CR in relatively good-risk AML patients was endorsed for years by the Acute Leukemia French Association (ALFA), we had the opportunity to analyze the results associated with this strategy. With the aim to evaluate the role of delayed SCT, we thus performed the present study reviewing the outcome of these patients once the first relapse occurred. In all, 92 relapsing patients with either CBF-AML or AML with a normal karyotype initially enrolled in two prospective ALFA trials were included.
Patients and methods
The study was conducted in 92 consecutive first relapsing patients, aged less than 50 years, with AML of favorable cytogenetics (CBF group, including t(8,21) and inv(16)/t(16,16)) or normal karyotype (NN group), and initially randomized in the two successive ALFA-9000 and ALFA-9802 trials. These patients must have been considered a priori as eligible for allogeneic SCT from a sibling donor in second rather than first CR based on the following additional criteria: (1) first CR reached in one induction course only; (2) age >35 years and WBC <100 × 109/l for NN patients; and (3) WBC <100 × 109/l for t(8;21) patients included in the most recent ALFA-9802 trial. Search for a sibling donor was performed before relapse in all patients. Standard cytogenetic techniques and criteria were used.12 Presence of an internal tandem duplication of the FLT3 gene (FLT3-ITD) was not considered for patient selection, but retrospectively assessed on a diagnosis sample in a subset of 50 patients using genomic polymerase chain reaction, as described.13
As reported previously,14 patients from the ALFA-9000 trial (April 1990–February 1996) were randomized to receive one of the three following reinforced induction regimens: (1) Arm A: a standard 3+7 induction course including high-dose daunorubicin (80 mg/m2/day for 3 days); (2) Arm B: a double induction with a second induction course comprising mitoxantrone and cytarabine starting at Day 20 of this 3+7 regimen; (3) Arm 3: a timed-sequential induction course consisted of daunorubicin and cytarabine for 3 days followed by mitoxantrone and cytarabine for 3 days, starting at Day 8 of the first sequence. Patients not eligible for allogeneic SCT in first CR received then two courses of consolidation. The first mild consolidation course comprised amsacrine for 1 day and subcutaneous cytarabine for 5 days. The second consolidation course was an intensive timed-sequential EMA regimen comprising mitoxantrone, etoposide and cytarabine, as described previously.14, 15 All patients from the subsequent and still ongoing ALFA-9802 trial (activated in April 1999) received the timed-sequential ALFA-9000 induction. Patients not eligible for allogeneic SCT in first CR were then randomized to receive either the entire ALFA-9000 consolidation schedule (Arm A) or the entire high-dose cytarabine (HDAC) consolidation arm of the Cancer and Leukemia Group B (CALGB) study (Arm B).16 Since November 2000, this second randomization did not concern patients with t(8;21) AML who were all allocated to the CALGB HDAC arm. Numbers of patients according to initial trial and randomization arm are given in Table 1.
Salvage therapy used for second CR induction in the 92 patients of the present study was mostly an HDAC-containing course (79 patients) or a timed-sequential course again (10 patients). Very few patients received gemtuzumab ogozamicin (three patients). In patients without a donor, intensive consolidation chemotherapy usually comprised one or two HDAC courses with or without anthracyclins. A few patients received an autologous SCT in second CR (eight patients) with stem cells collected in second CR. Conversely, no intensive chemotherapy was planned to consolidate the second CR in patients with a donor. These patients received one to three mild consolidation courses before allogeneic SCT. In some of these relapsing patients, a search for a matched unrelated donor (MUD) was performed. A MUD was identified in 12 patients who reached the second CR and eight of them were actually transplanted in second RC.
Hazard ratios (HR) were obtained using the maximum-likelihood model and given with 95% confidence interval (CI). The following factors were considered in multivariate analysis: presence of an identified sibling donor; presence of FLT3-ITD; and duration of first CR. Other potential variables such as age, white blood cell count (WBC) at diagnosis, initial trial and randomization arms, as well as salvage regimens were not considered, because of the absence of significant impact on second CR achievement and post-relapse survival in the univariate setting. In all analyses, patients with an identified MUD were considered as belonging to the no-donor group, whatever they were transplanted in second CR or not. This was based on the fact that the MUD vs no-MUD item was not available before relapse in all patients without identified sibling donor. Survival data were estimated by the Kaplan–Meier method and compared using the log-rank test. In multivariate analysis, outcome comparisons were adjusted using the Cox model. Results reported here are based on follow-up data as of September 2003. All calculations were performed using the Stata software, version 7.0 (Stata Corporation, College Station, TX, USA).
A total of 136 of the 282 CR1 patients aged <50 years enrolled in the ALFA-9000 trial experienced a relapse as first event.14 According to patient selection criteria mentioned above, 68 of these 136 patients were included in the present study (22 CBF and 46 NN). Until April 2002, 177 of the 201 patients aged <50 years enrolled in the ALFA-9802 trial reached first CR. Among these patients, 51 experienced a relapse as first event before March 2003. According to patient selection criteria mentioned above, 24 of these 51 patients were included in the present study (10 CBF and 14 NN). We thus report on a total population of 92 selected patients with AML in first relapse.
The CBF group included 32 patients (20 t(8;21) and 12 inv(16) AML; median age, 34 years; median WBC, 22 × 109/l; median CR1 duration, 10.5 months; 11 patients with identified sibling donor). The NN group included 60 patients (median age, 39 years; median WBC, 13 × 109/l; median CR1 duration, 10.5 months; 20 patients with identified sibling donor). FLT3 status was studied in 17 CBF and 33 NN patients and FLT3-ITD was detected in 0 CBF and 14 NN cases. Median duration of first CR duration was significantly shorter in FLT3-ITD as compared to FLT3-wild-type (FLT3-wt) NN patients (6.4 vs 16.7 months, P=0.05).
Second CR achievement
In all, 61 patients (66%) achieved a second CR (22/32 CBF and 39/60 NN; P=0.82). The rate of second CR was comparable in patients with or without identified sibling donor (40/61 patients without donor vs 21/31 patients with a donor including 8/11 CBF and 13/20 NN; P=0.99). Prognostic analysis is shown in Table 2. Duration of first CR was found as a significant prognostic factor for second CR achievement (optimal cutoff, 10 months). However, in NN patients studied for FLT3 status, the rate of second CR was significantly lower in FLT3-ITD as compared to FLT3-wt patients (4/14 vs 15/19; P=0.005) and FLT3-ITD remained the only bad-prognostic factor for second CR achievement in multivariate analysis in these patients (Table 2).
With a median post-relapse follow-up of 7 years, the median post-relapse survival of the entire cohort was 10 months with an estimated 5-year survival at 17% (95% CI, 10–26%). Prognostic analysis is shown in Table 2. Not surprisingly, a first CR duration more than 10 months was again identified as good-risk factor for survival (P<0.001). In multivariate analysis, a longer first CR (P<0.001) and the presence of an identified sibling donor (P=0.03) were independent prognostic factors for longer survival in the whole patient population (Table 2). Of interest, these two factors remained independent in CBF patients, while not in NN patients (Table 2). In intention-to-treat analyses, estimated 5-year survival was 15% (95% CI, 4–33%) in the no-donor group vs 42% (95% CI, 13–68%) in the donor group for CBF patients and 10% (95% CI, 3–22%) in the no-donor group vs 23% (95% CI, 7–44%) in the donor group for NN patients (Figure 1).
Partly because of the lower rate of second CR, FLT3-ITD badly influenced the post-relapse survival of NN patients studied (P=0.004; Figure 2). In multivariate analysis, FLT3-ITD was the only bad-prognostic factor for post-relapse survival in these patients (P=0.01), while a borderline impact of CR1 duration was still noted (P=0.06) (Table 2).
Outcome of patients actually transplanted in CR2
Overall, 18 of the 31 patients with a donor were actually transplanted in CR2 (8/11 CBF and 10/20 NN). Their estimated 5-year post transplant survival was 49% (95% CI, 23–71%). In the 13 remaining patients, reasons for no SCT were non achievement of a second CR (three CBF and eight NN patients) or donor or recipient refusal (two NN patients). As none of the four NN patients with FLT3-ITD who reached CR2 had a donor, it was not possible to assess the outcome of FLT3-ITD patients according to SCT in CR2 or not.
As search for a MUD was mostly performed after relapse and not well controlled by study criteria, it was not possible to consider a larger group including all the 43 patients with either a related (31 patients) or an unrelated (12 patients) donor for a formal donor vs no-donor comparison. However, when taking into account the eight out of 12 patients with an MUD actually transplanted in CR2 (all from the NN subgroup), the estimated 5-year post transplant survival of the 26 transplanted patients was only 36% (95% CI, 17–55%). As a matter of fact, only one of the eight patients transplanted with an MUD was a long survivor (not shown).
Literature on the response to salvage therapy and survival of adults with first relapsing AML is relatively limited. In addition, previous reports usually analyzed the outcome of relapsing patients with AML in general.17, 18, 19, 20, 21 A recurrent observation, also found in the present study, was that the duration of first CR strongly influenced second CR achievement and survival from reinduction.17, 18, 19, 20, 21 In a large even if quite old study from Houston, duration of the initial remission positively correlated with a favorable karyotype including inv(16), t(8;21) and t(15;17) as well as with a lower incidence of antecedent hematologic disorders, high WBC and elevated creatinine or lactic acid dehydrogenase level.17 In a more recent study from Vienna, favorable or normal cytogenetics was also associated with a better outcome after second CR.20 Larger multivariate analyses are warranted to assess the relative impact of initial CR duration and cytogenetics. Of importance, the type of salvage treatment did not appear to be a factor significantly associated with prognosis, at least when effective antileukemic regimens were considered.18, 20 Lastly, donor availability was not considered as a potential prognostic factor in these reports, probably due to a common strategy of SCT in first CR in patients with a donor.
Conversely, the aim of the present study was to analyze prognostic factors for second CR achievement and survival from relapse in a selected and thus obviously limited homogeneous subset of patients systematically not considered for SCT in first CR. Selection criteria used for years by our group to define patients eligible for such a transplant strategy have been recently validated by two important and complementary prospective studies conducted in first CR by the EORTC-GIMEMA and the MRC groups.8, 9 In the EORTC-GIMEMA study, patients with either CBF-AML or AML with a normal karyotype or a deletion of one Y chromosome had similar leukemia-free survival whether they belonged to the donor or the no-donor group.9 For a long time, however, it has been suspected that the subset of AML with a normal karyotype is not associated with a homogeneous prognosis. We know now that molecular abnormalities involving several genes such as FLT3,22, 23, 24 MLL,25 CEBPA,26, 27, 28 EVI129 or BAALC30 negatively or positively influence the outcome of these patients. Molecular detection of these abnormalities was not prospectively considered for patient selection in the present study. However, since 2002, we prospectively detect MLL rearrangements and FLT3-ITD in order to propose SCT in first CR in these high-risk patients. In a similar way, we are currently setting up a prospective detection of good-prognostic CEBPA mutations and bad-prognostic EVI1 expression with the aim to also use these factors for SCT stratification.
In conclusion, the two main results of the present study are the positive impact of a sibling donor availability in patients with first relapsing CBF-AML on the one hand and the marked negative impact of initial FLT3-ITD in patients with first relapsing AML with a normal karyotype on the other. The improved survival of patients with CBF-AML observed here in the donor group while not reported in newly diagnosed CBF-AML patients further supports the place of SCT in second CR in this AML subset. Frequent failure to achieve second CR in patients with FLT3-ITD AML with a normal karyotype validates our current strategy, which consider SCT in first CR in those with a donor. Larger specific studies are needed to define the best option in patients with AML with a normal karyotype and no FLT3-ITD. Other gene mutations and maybe gene-expression profiles have to be taken into account in this patient population.
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de Labarthe, A., Pautas, C., Thomas, X. et al. Allogeneic stem cell transplantation in second rather than first complete remission in selected patients with good-risk acute myeloid leukemia. Bone Marrow Transplant 35, 767–773 (2005). https://doi.org/10.1038/sj.bmt.1704884
- acute myeloid leukemia
- allogeneic stem cell transplantation
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