Karyotype is an independent prognostic parameter in therapy ... - Nature

Leukemia (2004) 18, 120–125 & 2004 Nature Publishing Group All rights reserved 0887-6924/04 $25.00 www.nature.com/leu

Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML C Schoch1, W Kern1, S Schnittger1, W Hiddemann1 and T Haferlach1 1 Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany

The aim of this study was to compare the pattern of karyotype abnormalities of therapy-related acute myeloid leukemia (tAML) (n ¼ 93) with de novo AML (n ¼ 1091), and to evaluate their impact on prognosis. Favorable, intermediate, and unfavorable cytogenetics were observed in 25.8, 28.0, and 46.2% of t-AML, and in 22.2, 57.3, and 20.4% of de novo AML. The median overall survival (OS) was shorter in t-AML than in de novo AML (10 vs 15 months, P ¼ 0.0007). Favorable and unfavorable cytogenetics had a prognostic impact with respect to OS in both t-AML (P ¼ 0.001 and 0.0001) and de novo AML (Po0.0001 and o0.0001). To define the overall prognostic impact of cytogenetics and t-AML, a multivariate Cox’s regression analysis was performed for OS with favorable cytogenetics, unfavorable cytogenetics, t-AML, age, and white blood cell (WBC) count as covariates. All parameters proved to be independently related to OS (P ¼ 0.001 for t-AML, Po0.0001 for all other parameters). Within patients with t-AML, there were significant correlations between OS and both unfavorable (Po0.0001) and favorable cytogenetics (P ¼ 0.001), while age and WBC count had no impact on OS. In conclusion, these data indicate that cytogenetics are an important prognostic parameter in t-AML. Furthermore, t-AML is an unfavorable factor independent of cytogenetics with respect to survival. Leukemia (2004) 18, 120–125. doi:10.1038/sj.leu.2403187 Published online 30 October 2003 Keywords: acute myeloid leukemia; therapy-related AML; cytogenetics; prognosis

Introduction About 10–15% of acute myeloid leukemia (AML) arise secondary after chemotherapeutic treatment and/or radiation for a primary malignancy and are therefore called therapyrelated AML (t-AML).1 Compared to de novo AML, the incidence of clonal chromosome abnormalities in t-AML is higher. In 68–96%, karyotype aberrations are detected (Schoch et al. Blood 1999; 94(Suppl. 1): 273a; abstract).2–6 The spectrum of karyotype aberrations is comparable to de novo AML but distribution varies, as 11q23 abnormalities and complex aberrant karyotypes occur more often in patients with t-AML (Schoch et al. Blood 1999; 94(Suppl. 1): 273a; abstract).7–9 Depending on whether the patient has received alkylating agents or drugs targeting topoisomerase II, t-AMLs are usually divided into two groups. This division based on etiological criteria is associated with a specific karyotype pattern and other biological parameters. Alkylating agents-related t-AML are characterized frequently by a preceding myelodysplastic phase, a long interval between cytotoxic treatment and appearance of Correspondence: Dr C Schoch, Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians University of Munich, Marchioninistr. 15, Mu¨nchen 81377, Germany; Fax: þ 49 89 7095 4971; E-mail: [email protected] Received 14 July 2003; accepted 10 September 2003; Published online 30 October 2003

t-AML (36–72 months), cytogenetic abnormalities involving chromosomes 5 and 7, and complex aberrant karyotypes showing a poor response to chemotherapy. t-AMLs related to therapy with topoisomerase II inhibitors usually present with overt leukemia without a myelodysplastic phase, with AML M4 or M5 according to FAB classification, have a short latency period (6–36 months), show balanced chromosome aberrations, primarily translocations involving chromosome bands 11q23 and 21q22, and a more favorable response to chemotherapy.7,10–18 Translocations involving 11q23 predominate following therapy with epipodophyllotoxins, whereas patients with translocations to 21q22, inv(16), and t(15;17) most often have received anthracyclines.13,18,19 However, a multivariate analysis in a large series of patients with t-AML and balanced translocations showed that younger age, and not a specific type of DNA topoisomerase II inhibitor, seems to predispose to the development of t-AML with 11q23 translocation.20 In accordance with these data, in a series of 48 cases with t-AML, patients with balanced chromosome aberrations such as t(8;21), inv(16), t(15;17), or t(11q23) were significantly younger than patients with other abnormalities (median 45 vs 60 years) and showed a shorter latency period between the primary tumor and t-AML (30 vs 81 months) (Schoch et al. Blood 1999; 94(Suppl. 1): 273a; abstract). Overall, t-AMLs respond less well to treatment than their de novo counterparts. Recent data suggest that as in de novo AML, cytogenetics are also an important prognostic factor in t-AML (Schoch et al. Blood 1999; 94(Suppl. 1): 273a; abstract).2,9,21,22 But compared to de novo AML, only little is known about the prognostic impact of cytogenetics in t-AML. The present study demonstrates that the karyotype of the leukemic blasts is an independent prognostic parameter in t-AML.

Material and methods

Patient material Between January 1996 and August 2001 in 1749 patients with newly diagnosed de novo AML or t-AML, cytogenetics were successfully performed in our laboratory. AMLs after an antecedent hematological disorder diagnosed in the same time frame were excluded from the present study (n ¼ 148). For 93 of 117 (79.5%) patients with t-AML and for 1091 of 1632 (66.8%) de novo AML cases, clinical follow-up data were available. These cases are the basis for the present analysis. In all, 53 of 93 patients (56.9%) with t-AML and 1037 of 1091 cases (95.1%) with de novo AML were treated within the AMLCG 1992, AMLCG 1999, and AMLCG APL trials, respectively, while the others were treated with comparable intensive therapies.23–25 AMLs were categorized as t-AML if patients had been treated with either chemotherapy and/or radiotherapy prior to diagnosis of AML for a primary disease. In order to assign an AML to the

Prognostic impact of karyotype and t-AML C Schoch et al

121 group of de novo AML, the patient must not have received any chemotherapeutic treatment, radiotherapy, and no antecedent hematological disorder was diagnosed before. Patients with tAML who died from the primary tumor were excluded, as one aim of this study was to evaluate the prognostic impact of t-AML. Patients were grouped according to cytogenetics into three categories: (1) Favorable: t(8;21), inv(16), t(15;17). (2) Intermediate: normal, other abnormalities. (3) Unfavorable: 3q21q26 abnormalities, 5q/5, 7q/7, 11q23 abnormalities, 12p abnormalities, 17p abnormalities, complex aberrant karyotypes (X3 abnormalities, excluding cases with t(8;21), inv(16), and t(15;17))

Table 1 novo AML

Frequency of karyotypes in t-AML compared to de

Karyotype t(8;21) inv(16) t(15;17) Normal Other abn 11q23 Complex aberrant Other unfavorable

t-AML (n ¼ 93) 6 13 5 13 13 12 25 6

(6.4%) (14.0%)* (5.4%) (14.0%)** (14.0%) (12.9%)** (26.9%)** (6.4%)

De novo AML (n ¼ 1091) 82 73 87 463 163 40 123 60

(7.5%) (6.7%)* (8.0%) (42.4%)** (14.9%) (3.7%)** (11.3%)** (5.5%)

*P ¼ 0.009. **Po0.001

Cytogenetics Cytogenetics were performed as described elsewhere.26 In all cases, 15–30 metaphases were analyzed and classified according to the International System for Human Cytogenetic Nomenclature.27

Statistics Overall survival (OS) was defined as the time from diagnosis of AML until death and was calculated according to Kaplan– Meier,28 and the differences between groups were analyzed using the log-rank statistics.29 Univariate and multivariate analyses were performed applying the Cox model. All P-values reported are two sided. All calculations were performed using SPSS 11.0.1.

RESULTS

Figure 1 OS of 1091 patients with de novo AML compared to 93 patients with t-AML.

Patient characteristics In t-AML, the median age was 57 years (range 16–82 years); in de novo AML the median age was 58 years (range 16–84 years). In t-AML, 39 patients (42%) were male and 54 (58%) female. In the cohort of de novo AML, 655 (60%) were male and 436 (40%) female. The median white blood cell count was 5190/ml (range 600–163 000/ml) in t-AML and 15 500 (range 200– 563 000/ml) in de novo AML (P ¼ 0.0004). Primary diseases in cases with t-AML were breast cancer (n ¼ 25), Hodgkin’s lymphoma (n ¼ 16), non-Hodgkin’s lymphoma (n ¼ 15), testicular cancer (n ¼ 6), autoimmune disease (n ¼ 6), multiple myeloma (n ¼ 4), thyroid cancer (n ¼ 4), ovarian cancer (n ¼ 3), lung cancer (n ¼ 2), colon cancer (n ¼ 2), neuroendocrine tumor (n ¼ 2), head and neck cancer (n ¼ 2), thymoma (n ¼ 2), cervix cancer (n ¼ 1), melanoma (n ¼ 1), sarcoma (n ¼ 1), and T-ALL (n ¼ 1). The median latency period between the diagnosis of the primary disease and the diagnosis of t-AML was 47 months (6–264 months).

Cytogenetics An aberrant karyotype was detected in 86% of t-AML and in 57.6% of de novo AML (Po0.00001). Balanced translocations involving bands 11q23/MLL and 21q22 were observed in 18 cases of t-AML (19%) and in 125 cases of de novo AML (11.5%) (P ¼ 0.025). Other balanced rearrangements (ie inv(16), t(15;17),

other rare ones) occurred in 23 cases of t-AML (24.7%) and in 192 cases of de novo AML (17.6%) (P ¼ 0.09). Favorable, intermediate, and unfavorable cytogenetics were observed in 25.8, 28.0, and 46.2% of t-AML and in 22.2, 57.3, and 20.4% of de novo AML, respectively (favorable: NS; intermediate: Po0.00001; unfavorable: Po0.00001). The frequencies of the major cytogenetic abnormalities are shown for t-AML compared to de novo AML in Table 1.

Prognostic impact of t-AML and cytogenetics The median OS of 1091 de novo AML was 15 months, while it was only 10 months in t-AML (P ¼ 0.0007). The respective survival curves are shown in Figure 1. The rates of complete remission were significantly lower in t-AML as compared to de novo AML in the group of cases with intermediate and unfavorable karyotype, but did not differ in patients with favorable cytogenetics. Overall, no significant differences in the relapse rate were observed between de novo and t-AML. However, in the group with favorable cytogenetics the relapse rate was significantly higher in t-AML (33 vs 13%, P ¼ 0.01). In an univariate Cox’s regression analysis, favorable and unfavorable cytogenetics had prognostic impact with respect to OS in both t-AML (P ¼ 0.001 and 0.0001) and de novo AML (Po0.0001 and o0.0001). Leukemia


122 up to now. In AML with inv(16), the median OS was neither reached in the t-AML nor in the de novo AML group. The OS rate at 5 years was 61.5% in t-AML as compared to 77.8% in de novo AML (P ¼ 0.33). In t-APL median, OS was 26.3 months vs not reached in de novo APL and the OS rate at 5 years was 87.5% for de novo cases and none of the t-APL cases has reached 5 years so far (P ¼ 0.051). Univariate Cox’s regression analyses in the total cohort of patients (t-AML and de novo AML combined) resulted in significant correlation of age, white blood cell count, t-AML, favorable cytogenetics, and unfavorable cytogenetics, respectively, with OS (Po0.001, P ¼ 0.004, P ¼ 0.001, Po0.001, and Po0.001, respectively). Of these parameters, only favorable and unfavorable cytogenetics were significantly related to OS in univariate Cox regression analyses when only the cohort of patients with t-AML was analyzed (P ¼ 0.001, and Po0.001, respectively). Figure 2 OS of 93 patients with t-AML according to cytogenetic risk groups.

Multivariate analysis To define the overall prognostic impact of cytogenetics and tAML in the total cohort of AML patients, a multivariate Cox regression analysis was performed for OS with favorable cytogenetics, unfavorable cytogenetics, t-AML, age, and white blood cell (WBC) count as covariates. All parameters proved to be independently related to OS (P ¼ 0.001 for t-AML, Po0.0001 for all other parameters).

Impact of treatment within clinical trials

Figure 3 OS of 1091 patients with de novo AML according to cytogenetic risk groups.

The median OS for patients with t-AML and favorable, intermediate, and unfavorable cytogenetics was: 18, 11, and 6 months, respectively (Figure 2). The respective data in de novo AML were: not reached, 14 months, and 6 months, respectively (Figure 3). Within the group of patients with favorable cytogenetics, cases with t-AML showed a significantly shorter median OS than those with de novo AML (18 months vs not reached, P ¼ 0.006), while the differences in OS were smaller within the groups with intermediate and unfavorable cytogenetics (t-AML vs de novo AML: 11 vs 14 months, P ¼ 0.31; 6 vs 6 months, P ¼ 0.06, respectively). Furthermore, within the favorable group we analyzed cases with t(8;21), inv(16), and t(15;17) separately, and compared the outcome within these distinct cytogenetic subgroups between t-AML and de novo AML. In all, three subgroups’ outcome of t-AML cases was inferior compared to de novo AML. AML with t(8;21) showed the worst outcome with a median OS in t-AML of 14 months as compared to 25.5 months in de novo AML (P ¼ 0.14). In de novo AML, 38% of cases were alive at 5 years, while none of the t-AML cases had reached this long follow-up Leukemia

In the analyzed cohort, 53 of 93 patients (56.9%) of t-AML cases were treated within an AMLCG trial. In the overall cohort as well as in the subgroups of patients with favorable or intermediate karyotypes, there was no difference in the OS between patients within clinical trials and those not treated within clinical trials (P40.05 in all comparisons). In cases with unfavorable karyotype, patients treated within clinical trials had a significantly longer OS (median OS 8.9 vs 1.6 months, P ¼ 0.033). Whether a selection bias or differences in therapy intensity are responsible for this difference is unclear.

Discussion The proportion of t-AML within the whole cohort of AML is difficult to determine, as frequently studies combine t-AML and AML following MDS as secondary AML. Most frequently, it is reported that t-AML accounts for 10 to 20% of all AML cases.10,30 In a population-based, consecutive, unselected series of 372 AML, 13% were reported to be t-AML.5 In our series, the proportion of t-AML was 6.2%. Within the MRC AML, 10, 11, and 12 trials t-AML account for only 2.3%. Therefore, a selection bias within clinical trials under-representing t-AML has to be suspected (Goldstone et al, Blood, 2002; 100(Suppl 1): 88a; abstract). No differences were observed in the median age between t-AML and de novo AML in our series (57 vs 58 years). The median age of our t-AML cases is within the range reported by other large series.5,6 The median latency between diagnosis of the primary disease and occurrence of t-AML was 47 months in our cohort. This is comparable to the data published by others.6 Several studies indicate that latency is significantly shorter in t-AML with balanced rearrangements as compared to all other cases.6


123 Aberrant karyotypes were observed in 86% of t-AML cases as compared to 57.6% in de novo AML. This is in line with data from the literature reporting on clonal chromosome aberrations in 68% to 96% of therapy-related cases (Schoch et al, Blood, 1999; 94(Suppl 1): 273a; abstract),2–6 and in 52% to 60% of de novo AML.31–34 The spectrum of cytogenetic aberrations is comparable in t-AML and de novo AML, but different frequencies of distinct cytogenetic categories are observed depending on the characteristics of the analyzed patient cohort and, especially on the age distribution and the ethnic composition.35–38 In addition, in t-AML the frequencies of specific chromosome abnormalities are associated with the therapy applied for the primary tumor.5,11,13,16,20,38 In our series, 44% of all t-AML showed recurring balanced translocations, in 42% of these an involvement of chromosome bands 11q23/MLL and 21q22 was observed, which is considered to be associated with prior treatment with topoisomerase II inhibitors. A comparable distribution was reported from the International Workshop on balanced translocations in t-MDS and t-AML, with 241 out of 511 cases (47%) showing involvement of chromosome bands 11q23 and 21q22, respectively.38 In the present series, the proportion of favorable karyotypes was comparable in t-AML and de novo AML while unfavorable karyotypes, and cases with complex aberrant karyotypes in particular, were significantly more frequent in t-AML. These data are in accordance with a cohort of 155 t-AML reported by the MRC group using a slightly different definition of cytogenetic subgroups; the proportion of favorable cytogenetics is also comparable between t-AML and de novo AML (19% and 21%, respectively), while the frequencies of unfavorable cytogenetics were 11% vs 27% in de novo AML vs t-AML (Goldstone et al, Blood, 2002; 100(Suppl. 1): 88a; abstract). Within therapeutic trials, AMLs following MDS and AML related to prior therapy (t-AML) are often analyzed together as secondary AML, thus precluding a judgment on the prognostic impact of t-AML. However, some trials show that t-AMLs in general respond less well to treatment than their de novo counterparts.39,40 This is confirmed by data from the present study showing a median OS of 10 months for 93 patients with t-AML and of 15 months for 1091 de novo AML. Results from MRC AML 9 trial also demonstrated a significantly lower CR in tAML as compared to de novo cases; however, the OS did not differ significantly.41 Data from more recent MRC trials show a worse OS of t-AML compared to de novo AML (OS 30% vs 44%) (Goldstone et al, Blood, 2002; 100(Suppl 1): 88a; abstract). In several large clinical trials, it has been demonstrated that the karyotype of the leukemic blasts is the most important prognostic factor in de novo AML (Grimwade et al, Blood, 2000; 96(Suppl1): 825a; abstract).31–34,42 Recent data suggest that cytogenetics are also an important prognostic factor in t-AML (Schoch et al, Blood, 1999; 94(Suppl 1): 273a; abstract);2,6,9,21,43 however, these analyses are based only on a small number of patients. The present analysis adds convincing evidence on the prognostic impact of cytogenetics in t-AML in a large number of patients using a cytogenetic categorization system (favorable, intermediate, unfavorable), which is also used in de novo AML. In t-AML, the OS was significantly different between the three cytogenetic groups as has also been shown for de novo AML. Favorable and unfavorable cytogenetics proved to be powerful prognostic factors independent of age and WBC count. As cytogenetics are a major prognostic factor in de novo as well as in t-AML, it can be speculated that the overall more unfavorable prognosis of t-AML as compared to de novo AML can partially be assigned to the fact that unfavorable karyotypes are more frequently observed in t-AML than in de novo AML. To

test this hypothesis, we performed a multivariate analysis for OS with favorable cytogenetics, unfavorable cytogenetics, t-AML vs de novo AML, as well as age and WBC count as covariates. All tested parameters proved to be independently related to OS, indicating that t-AML has an unfavorable influence on survival independent of unfavorable cytogenetics. Data from the MRC AML 10, AML 11, and AML 12 clinical trials demonstrated an independent prognostic impact for secondary AML (defined as the combination of t-AML and secondary AML after antecedent hematological disorder and MDS). The differences in survival between patients with secondary vs de novo AML appeared to exist for all age groups. The prognosis of patients with t-AML appeared to be more favorable compared to MDS or AML secondary to prior hematological malignancy (Goldstone et al. Blood 2002; 100(Suppl. 1): 88a; abstract). Furthermore, we compared the outcome of t-AML vs de novo AML within the different cytogenetic risk groups. In contrast to Goldstone et al, who reported a worse outcome of secondary AML (combining 155 t-AML with 385 MDS, 138 AML secondary to a prior hematological malignancy, and 82 with secondary leukemia of other antecedent cause) for all cytogenetic risk groups, we observed no statistically significant differences in OS within the unfavorable and intermediate risk group. Only in the favorable subgroup patients with t-AML showed a significantly shorter OS as compared to de novo AML. The higher incidence of uncommon secondary chromosome aberrations in these t-AML compared to de novo AML (Schoch et al. Blood 1999; 94(Suppl. 1): 273a; abstract) cannot explain the worse outcome, as a study on 44 cases with t-AML and t(8;21) showed no difference in outcome between cases with and without additional karyotype aberrations.44 In 48 cases with t-AML and inv(16) and 44 t-AML with t(15;17) also, no prognostic impact of secondary chromosome aberrations was observed.45 t-AMLs are often excluded from therapeutic trials and therefore are treated on a more individual basis that might be less intensive, although in this study treatment within a clinical trial did not influence outcome in patients with favorable karyotype. In this study, no differences in the CR rate were observed between t-AML and de novo AML and favorable cytogenetics, but the relapse rate was nearly three-fold in t-AML as compared to de novo AML. It can be speculated that still unknown molecular alterations in t-AML lead to these biological differences. Especially in APL, it has been reported that patients with therapy-associated disease have a favorable outcome comparable to de novo cases.9,21 In the present study, median OS of t-APL cases was 26 months, which is inferior compared to de novo cases, although not significantly. In another series of 35 cases with t-APL median, OS was 29 months and the probability of survival was 43% at 5 years.45 In comparison, 50% of de novo APL cases were long-term survivors in studies before the introduction of ATRA and about 75% in trials using ATRA in addition to chemotherapy.24,46–49 In the t-APL study published by Anderson et al, several but not all cases had received ATRA. In a direct comparison of 641 de novo APL cases and 51 APL cases occurring as a second malignancy treated within the GIMEMA trials, no significant differences in outcome were observed between both groups. The same was demonstrated in the subgroup of patients treated with ATRA (641 de novo APL and 31 secondary APL) showing a 4-year OS rate of 78% in de novo APL and 65% in secondary APL, respectively.50 In patients of the present series with inv(16), the OS rate at 5 years in the t-AML cohort was 61.5% compared to 77.8% in de novo AML cases with inv(16); median OS had not been reached in both groups. The difference between both groups was Leukemia


124 statistically not significant. Survival data of inv(16) reported from the International Workshop on balanced translocations in t-AML showed a median OS of 29 months and an OS rate at 5 years of 48%.45 From the recent CALGB series, median OS in de novo AML with inv(16) was reported to be 95 months.31 The OS rate at 5 years was 57% in the CALGB 8461 trial and 61% in the MRC 10 trial.31,32 In the present study, patients with t(8;21) showed the poorest outcome within the favorable group. The median OS for t-AML cases was 14 months as compared to 25.5 months for the de novo cases. The OS rate at 5 years was 38% in the de novo group and not evaluable in the t-AML group due to the small number of cases, as none of the patients had reached this followup time. The median OS of t-AML cases with t(8;21) as the sole abnormality and for cases with t(8;21) and additional chromosome aberrations was comparable (17.0 and 30.9 months, NS) as reported from the International Workshop on balanced translocations in t-AML.44 The respective data from de novo clinical trials show a median OS of 61 months31 and an overall survival rate at 5 years of 52 and 59%, respectively.31,32 Overall, t-AMLs with favorable cytogenetics show an inferior outcome compared to their de novo counterparts. In the present series, the median OS in t-AML was only 18 months as compared to not reached in de novo cases of this series and compared to 91 months and not reached in three studies reported from four large clinical trials on de novo AML. The respective numbers for the OS rate at 5 years for de novo AML are 67% for the current series and 65, 63, 55, and 55% from published trials.25,31,32,34 With respect to the intermediate and unfavorable cytogenetic risk group, the differences in outcome between de novo and tAML cases were smaller compared to the favorable risk group. While no published data on outcome are available for patients with intermediate and unfavorable cytogenetics and t-AML, outcome of de novo AML in the current series is comparable to published trials on de novo AML.25,31 In conclusion, this study indicates that in t-AML significant correlations of favorable and unfavorable cytogenetics with OS were observed, while age and WBC count had no impact on OS. Furthermore, t-AML is an unfavorable factor independent of cytogenetics with respect to survival. The negative prognostic impact of t-AML is strongest in patients with favorable cytogenetics.

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Acknowledgements The cell samples included in this study were sent for central diagnostics from various hospitals in Germany participating in the AMLCG trials (coordinators: T Bu¨chner and W Berdel, Mu¨nster; W Hiddemann, Mu¨nchen; B Wo¨rmann, Braunschweig, Germany; statisticians: A Heinecke, MC Sauerland, Mu¨nster, Germany). We thank the coordinators and the statisticians of this study for their continuous support, as well as all clinicians for providing cell samples and clinical data.

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