Cytogenetics-therapy correlations

The prognostic value of cytogenetics is reinforced by the kind of induction/consolidation therapy in influencing the outcome of acute myeloid leukemia – analysis of 848 patients

Abstract

We studied the impact of cytogenetics and kind of induction/consolidation therapy on 848 adult acute myeloid leukemia (AML) patients (age 15–83). The patients received three types of induction/consolidation regimen: standard (daunorubicin and cytosine arabinoside (3/7); two cycles); intensive (idarubicin, cytosine arabinoside and etoposide (ICE), plus mitoxantrone and intermediate-dose Ara-C (NOVIA)); and low-dose (low-dose cytosine arabinoside). CR patients under 60 years of age, if an HLA-identical donor was available received allogeneic stem cell transplantation (allo-SCT); otherwise, as part of the program, they underwent autologous (auto)-SCT. CR rates significantly associated with ‘favorable’ (inv(16), t(8;21)), ‘intermediate’ (‘no abnormality’, abn(11q23), +8, del(7q)) and ‘unfavorable’ (del (5q), −7, abn(3)(q21q26), t(6;9), ‘complex’ (more than three unrelated cytogenetic abnormalities)) karyotypes (88% vs65% vs 36%, respectively; P = 0.0001). these trends were confirmed in all age groups. on therapeutic grounds, intensive induction did not determine significant increases of cr rates in any of the considered groups, with respect to standard induction. low-dose induction was associated with significantly lower cr rates. considering disease-free survival (dfs), multivariate analysis of the factors examined (including karyotype grouping) showed that only age >60 years significantly affected outcome. However, in cases where intensive induction was adopted, ‘favorable’ karyotype was significantly related to longer DFS (P = 0.04). This was mainly due to the favorable outcome of t(8;21) patients treated with intensive induction. Patients receiving allo-SCT had significantly longer DFS (P = 0.005); in particular, allo-SCT significantly improved DFS in the ‘favorable’ and ‘intermediate’ groups (P = 0.04 and P = 0.048, respectively). In conclusion our study could provide some guidelines for AML therapy: (1) patients in the ‘favorable’ karyotype group seem to have a longer DFS when treated with an intensive induction/consolidation regimen, adopted before auto-SCT instead of standard induction; this underlines the importance of reinforcement of chemotherapy, not necessarily based on repeated high-dose AraC cycles. Allo-SCT, independently of induction/consolidation therapy, should be considered an alternative treatment; (2) patients in the ‘intermediate’ karyotype group should receive allo-SCT; (3) patients in the ‘unfavorable’ karyotype group should be treated using investigational chemotherapy, considering that even allo-SCT cannot provide a significantly longer DFS, but only a trend to a better prognosis.

Introduction

There is considerable debate on how the outcome of acute myeloid leukemia (AML) patients can best be improved.1,2,3,4,5 Until recently, treatment was based on a standard two-drug induction phase followed by various post-remission options, the intensity of which depended on the patient's age and eligibility for stem cell transplantation (SCT).3,4,5,6 Allogeneic (allo)-SCT is still generally considered the best option for patients with an HLA-identical donor. However, there is little agreement as to whether intensification of either induction or consolidation treatment can influence the duration of remission and survival.7,8 This situation may stem from the lack of diversified treatment schemes that take into account the biological heterogeneity of AML.9 Much effort has been made to identify prognostic factors. The FAB classification identifies the acute promyelocytic leukemia (APL) subtype (M3) of AML, which displays unique clinical features and marked sensitivity to all trans-retinoic acid and conventional chemotherapy based on anthracyclines.10,11 In addition, distinct trends have been found in the outcome of other AML subtypes, such as minimally differentiated (M0) AML and megakaryoblastic (M7) AML with trilineage myelodysplasia.12,13 Nevertheless, with the exception of APL, the FAB groupings seem to have little clinical relevance for initial therapeutic stratification. The most significant patient variable appears to be age, with older patients having a worse prognosis. The presence of a prior bone marrow disorder is also thought to affect outcome,14 whereas the value of the overall mass of leukemia, defined as the number of blasts or leukocytes, is still disputed.15 Taken together, these parameters are insufficient to identify the eventual outcome of many patients.

Cytogenetics is increasingly considered to be a relevant predictor of response to chemotherapy and clinical outcome.15,16,17,18 Two large multicenter studies19,20 have recently indicated that varying clinical outcomes can be predicted by detection at diagnosis of blasts of ‘unfavorable’, ‘intermediate’ or ‘favorable’ karyotype. One way of improving treatment strategy could be tailored induction and post-remission therapy based on genetic prognostic factors. Therapeutic trials are now being initiated to investigate different post-remission options on the basis of karyotype.16,19,21 Another issue that needs to be clarified is the impact of varying intensities of induction treatment on remission duration and survival.22,23,24

We thus retrospectively studied a non-randomized group of 848 AML patients enrolled and treated from 1990 to 1997 in 11 Italian centers, for whom cytogenetic analysis was available. We examined the impact of the most frequent cytogenetic abnormalities on complete remission (CR) rate and disease-free survival (DFS). We also observed the potential role of cytogenetics and other major prognostic factors with respect to standard, intensive and low-dose induction/ consolidation therapy.

Materials and methods

Patients

We reviewed 848 previously untreated AML (non-APL) patients over 15 years of age, diagnosed from January 1990 to December 1997 in 11 Italian institutions, for whom treatment response and survival duration data were available, as well as cytogenetic analysis at diagnosis. Clinical characteristics are reported in Table 1A. For the purpose of statistical analysis, the patients were subdivided into two age groups: 60 years (n = 615) and >60 years (n = 233). The morphological diagnosis of AML was determined by conventional morphological criteria, according to the FAB classification.25 Patients with diagnosis of APL were not included in the study as they were treated according to a specifically tailored protocol. Criteria for CR were normocellular bone marrow with normal hematopoiesis and <5% blast cells, with concomitant normal peripheral counts and no signs of extramedullary leukemia. DFS was considered as the interval between documentation of CR and first evidence of relapse.

Table 1a A Characteristics of 848 AML patients at diagnosis

Cytogenetics

Bone marrow for cytogenetic analysis was cultured according to standard methods. Twenty or more cells were fully analyzed to exclude clonal abnormalities, which were defined in accordance with the International System for Human Cytogenetic Nomenclature (ISCN) guidelines.26 For patients with a detectable clonal abnormality, at least 10 metaphases were examined to exclude secondary changes in accordance with national guidelines for clinical cytogenetics.27 Complex karyotype was defined as the presence of a clone with more than three unrelated cytogenetic abnormalities. The 848 patients for whom successful cytogenetic detection data were available corresponded to 82% of the 1034 cases of AML observed in the period. Herein we consider separately the categories of abnormalities found in at least 10 patients (Table 1B). In these analyses, each case was defined by the primary abnormality, as previously described,19 and was counted only once.

Table 1b B Karyotypes detected in 848 cases of AML grouped with respect to the outcome of patients

Therapeutic protocols

The participating centers all employed three types of induction/consolidation regimen: intensive, standard and low dose. As there was no demonstration of an advantage of either protocol, the centers were free to adopt, as center policy, the intensive or the standard induction/consolidation regimens. Briefly, intensive regimen consisted of induction with idarubicin (10 mg/m2 i.v. push per day on days 1, 3, 5), cytosine arabinoside (100 mg/m2/day in continuous infusion on days 1–10, preceded at the start of infusion by 100 mg bolus injection) and etoposide (100 mg/m2/day i.v. on days 1 to 5) (ICE); patients who achieved CR after ICE received high-dose NOVIA consolidation: cytosine arabinoside 500 mg/m2/twice a day on days 1–6; mitoxantrone 12 mg/m2/day on days 1–4. Standard therapy comprised daunorubicin (45 mg/m2 i.v. bolus on days 1–3) and cytosine arabinoside (200 mg/m2 in continuous infusion on days 1–7, preceded at the start of infusion by 100 mg bolus injection), based on the 3/7 scheme; patients who achieved CR received a second 3/7 scheme. The low-dose therapy was administered to patients older than 70 years. It consisted of cytosine arabinoside 15 mg/m2/12 h (subcutaneous injection) on days 1–12, administered twice.

Up to 55 years of age allo-SCT was performed, when an HLA matched donor was available. Up to 60 years of age, consolidation was reinforced by autologous (auto)-SCT whenever the performance status was considered adequate. After 60 years of age, post-consolidation treatment was only occasionally administered.

Statistical analysis

The last analysis was in August 1999. Patients who died in CR or who were lost to follow-up were considered censored observations at the time point when they were last observed. Events were relapse or death. DFS was calculated according to the Kaplan–Meier estimate.28 Comparison between the DFS curves was conducted by the log-rank test according to Peto et al.29 Analysis was performed using the BMDP Statistical Software 1990 Edition. Two-sided P values were used throughout. P values were considered significant when <0.05.

Results

Incidence of specific cytogenetic abnormalities

The frequency of the most common cytogenetic abnormalities detected at diagnosis are presented in Table 1B.

CR rates with respect to karyotype, therapy and other factors

CR rates with respect to cytogenetic abnormalities, karyotype groupings (‘unfavorable’, ‘intermediate’, ‘favorable’) and type of induction therapy are shown in Tables 2 and 3, respectively.

Table 2 CR rates according to cytogenetic risk groups and single abnormality
Table 3 CR rates according to induction therapy

Inv(16) and t(8;21) were associated with particularly high CR rates (91% and 86%, respectively). Abnormalities associated with extremely poor CR rates were abn(3)(q21q26), complex karyotype and del(5q) (CR rates 28%, 30% and 37%, respectively). Intermediate CR levels were found in the remaining categories: eg abn(11q23): 62% CR; no karyotypic abnormality: 69% CR; +8: 65% CR; del(7q): 62% CR. These findings are in line with the ‘unfavorable’, ‘intermediate’ and ‘favorable’ risk groups already reported.19,20 As can be seen from Table 2, CR rates significantly associated with the three groups (P = 0.0001). As regards therapy, intensive induction, with respect to standard induction, did not determine significant increases of CR rates in any of the three major karyotype groups, with the exception of the whole ‘intermediate’ group; the latter result, however, was not found among patients in the ‘intermediate’ karyotype group 60 years (data non shown).

Impact of cytogenetic abnormalities and kind of therapy on survival

Overall DFS is reported in Figure 1. The DFS with respect to the three karyotype groups is reported in Figure 2. Univariate analysis showed longer DFS in the ‘favorable’ karyotype group with respect to the ‘unfavorable’ one (P = 0.001) as well as in the ‘intermediate’ group with respect to the ‘unfavorable’ one (P = 0.03). Nevertheless, multivariate analysis showed that up to 60 years of age DFS did not significantly differ among the three different karyotype groups. Among the other prognostic factors examined at diagnosis (FAB subgroup, number of leukocytes, sex, organomegaly, or age), the only ones that influenced DFS at univariate analysis were organomegaly and age >60 years (P = 0.0001) (Figure 3).

Figure 1
figure1

DFS of 848 AML patients treated with low-dose, standard or intensive chemotherapy.

Figure 2
figure2

DFS of 848 AML patients with respect to three karyotype groups: ‘favorable’ (FAV), ‘intermediate’ (INT) and ‘unfavorable’ (UNFAV).

Figure 3
figure3

DFS of 848 AML patients with respect to age groups.

Concerning AML patients aged between 14 and 60 years, the type of induction therapy (low-dose, standard or intensive) significantly influenced DFS in certain karyotype subgroups (Figures 4–8). The ‘favorable’ karyotype group performed significantly better in terms of DFS when intensive induction with ICE was adopted (Figure 4; P = 0.04). This was mainly due to the favorable outcome of t(8;21) patients treated with intensive induction (DFS at 5 years: 80% intensive vs 14% standard; P = 0.003; Figure 5). By contrast, patients with inv(16) showed over 40% DFS in both therapeutic arms. In the ‘intermediate’ karyotype group, the type of induction therapy was not significantly associated with DFS. This was confirmed when the different karyotypic subgroups (eg ‘normal’ karyotype, abn(11q23), +8, del(7q), ‘other numerical’, ‘other structural’) were analyzed separately. The same applied in the ‘unfavorable’ karyotype group. However, in this group, a trend in favor of intensive therapy was observed, but, probably due to the relatively low number of patients, this did not reach significance. The number of cases receiving auto-SCT (n = 154) were comparable after the two types of induction.

Figure 4
figure4

DFS of patients aged 14–60 years and with ‘favorable’ karyotype with respect to kind of induction therapy (standard vs intensive) (n = 91).

Figure 5
figure5

DFS of patients aged 14–60 years and with t(8;21) with respect to kind of induction therapy (standard vs intensive) (n = 52).

Overall, patients receiving allo-SCT had significantly longer DFS (P = 0.005; Figure 6). In addition, allo-SCT was associated with significantly better DFS in patients in the ‘favorable’ and ‘intermediate’ karyotype groups (Figures 7 and 8; P = 0.04 and P = 0.048, respectively), independently of the kind of induction/consolidation therapy used. As regards the ‘unfavorable’ group, the DFS was longer after allo-SCT, but due to the small number of patients, this trend could not reach significance.

Figure 6
figure6

DFS of patients aged 14–60 years with respect to allo-SCT (n = 557).

Figure 7
figure7

DFS of patients aged 14–60 years and with ‘favorable’ karyotype with respect to allo-SCT (n = 99).

Figure 8
figure8

DFS of patients aged 14–60 years and with ‘intermediate’ karyotype (n = 445) with respect to allo SCT.

Discussion

Cytogenetics is now considered one of the most valuable prognostic determinants in AML. However, many of the studies on which this convinction is based were limited by relatively small sample size or varying therapeutic approaches. This has led to conflicting data regarding the prognostic implications of specific cytogenetic abnormalities. Two large multicenter studies,19,20 in which cytogenetics was available for the majority of the enrolled patients, have indicated a correlation between clinical outcome and detection at diagnosis of AML blasts of ‘unfavorable’, ‘intermediate’ and ‘favorable’ karyotype. It has been suggested that patients bearing favorable cytogenetic abnormalities could be spared highly toxic and life-threatening approaches such as allo-SCT, as they could achieve long-term remission with chemotherapy alone.19,20,21,22,23,24,25,26,27,28,29,30,31,32

A second point that needs to be clarified is the impact of induction/consolidation treatment on remission duration and survival. In the effort to improve results, the standard two-drug induction approach has been varied many times in the last 15 years as regards intensity, duration and combination.33,34,35,36 Addition of a third drug has resulted in contradictory effects. However, employment of high-dose cytarabine seems to improve outcome,7,8,21,24,37,38,39 without affecting the remission rates. This suggests that high-dose cytarabine provides a better quality of remission. The prolongation of induction with cytarabine treatment for 10 instead of 7 days is now a widely used strategy, although the possible superiority of this schedule has yet to be demonstrated in a randomized trial. Moreover, the best type of induction and consolidation treatment for patients with different cytogenetic characteristics has still to be determined.

In the present study, in a relatively large series of consecutive AML patients, we assessed the possible impact of the stratification of patients into three karyotype risk groups. Our results suggest that this stratification has a significant prognostic value in univariate analysis, especially in certain karyotype subgroups. However, this stratification seems somewhat limited analyzing data in multivariate analysis. As expected, CR rates turned out to be significantly higher in the ‘favorable’ group than in the ‘intermediate’ and ‘unfavorable’ group, and also in the ‘intermediate’ group as compared with the ‘unfavorable’ one. These trends were apparently independent of the use of intensive induction. Low-dose induction was associated with significantly lower overall CR rates with respect to those obtained with the intensive or standard forms. Considering DFS, only age >60 years was related to significantly poorer outcome. None of the other prognostic factors examined at diagnosis (including the three karyotypic subgroups) was independently related to significant differences in DFS. The negative impact of age on DFS may be related to the more frequent incidence of ‘unfavorable’ karyotypes in the elderly and to the generally poor performance status at diagnosis, which often prohibits the use of intensive chemotherapy schemes. These findings provide further evidence of the limitations of the currently available prognostic factors at diagnosis (including karyotype grouping), and highlight the need for more powerful indicators.

When the impact of the different therapies was considered, the ‘favorable’ subgroup turned out to be significantly related to longer DFS if intensive induction/consolidation was adopted. This finding appears to be specifically due to the favorable outcome of t(8;21) patients when treated with the intensive induction/consolidation regimen, whereas the DFS of inv(16) patients seemed to be unaffected by the kind of therapy employed. A favorable outcome, in t(8;21) cases, could thus be related not only with the number of repeated cycles of high-dose AraC as previously reported,40 but with alternative intensive chemotherapy schedules as well. In the ‘intermediate’ subgroup, intensive induction did not appear to improve DFS with respect to standard induction. On the other hand, use of intensive induction in the ‘unfavorable’ subgroup appeared to be associated with somewhat better DFS.

As regards the contribution of allo-SCT, this procedure seemed to exert a positive influence on DFS both in the ‘favorable’ and ‘intermediate’ karyotype group, independent of the kind of induction/consolidation therapy used, whereas we did not observe a significant different in the ‘unfavorable’ subgroup. Thus, whether or not survival improvements observed after allo-SCT reflect more effective therapy or represent patient selection still remains unclear.

These results seem to suggest that the prognostic value of karyotype groupings is somewhat limited. It is true that our findings derive from a retrospective study, albeit of a large series of consecutive patients treated with standardized therapeutic protocols. Furthermore, it could be argued that the use of auto-SCT affected the relative DFS with respect to specific abnormalities, even though the percentage of patients who underwent this procedure was similar in the three karyotype groups. However, among patients carrying t(8;21) the influence of auto-SCT seems to have been negligible. Our findings underline the validity of adopting intensive induction/ consolidation therapy without recourse to allo-SCT in patients with t(8;21) alteration.

In conclusion, our study shows that karyotype abnormalities do not influence the outcome of AML patients in multivariate analysis. However, it is evident that karyotype has a predictive value on CR rates and DFS in univariate analysis. Thus, it may provide some guidelines for AML therapy. In the ‘favorable’ karyotype group, the duration of DFS in t(8;21) patients appears to be favorably influenced by an intensive induction/consolidation regimen adopted before auto-SCT instead of standard induction, underlining the importance of a reinforcement of chemotherapy, not necessarily based on repeated high-dose Ara-C cycles; allo-SCT, independently of induction/consolidation therapy, should be considered an alternative treatment, able to determine equivalent results if compared to the previous approach. Inv(16) patients have a similar good prognosis, which does not seem to be influenced by the kind of induction/consolidation regimen adopted. Patients in the ‘intermediate’ karyotype group should receive allo-SCT whereas patients in the ‘unfavorable’ karyotype group should be treated using investigational chemotherapy, considering their poor prognosis when any other conventional therapy is used.

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Acknowledgements

This work was supported in part by MURST ex 40% (S Tura) and FONDI ex 60% (S Tura).

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Correspondence to G Visani.

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Keywords

  • acute myeloid leukemia
  • cytogenetics
  • chemotherapy

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