Clinical characteristics and outcomes in patients with t(8;21) acute myeloid leukemia in Japan

In acute myeloid leukemia (AML), t(8;21)(q22;q22) translocation is one of the most common karyotype abnormalities, occurring in 7–8% of adult patients.1 This change is closely associated with AML-M2 subtype in the French-American-British (FAB) classification, a type of AML with high complete remission (CR) rate (85–90%) and favorable survival rate.1, 2, 3 Studies conducted in western countries have demonstrated that survival is prolonged when consolidation chemotherapies comprising high-dose cytarabine are administered.2

A research group from the Cancer and Leukemia Group B reported that clinical characteristics of t(8;21) AML could alter depending on ethnicity, suggesting that direct adoption of treatment strategies based on clinical studies conducted in western countries to Japanese patients may not be advisable.4 A recent study from Japan focused mainly on the clinical impact of cytogenetics.5 Information on clinical characteristics and optimal treatments, such as the clinical impact of high-dose cytarabine, thus remains unavailable for Japanese patients.

To establish optimal therapeutic strategies applicable to Japanese patients, clarification of clinical characteristics and outcomes in Japanese patients with t(8;21) AML is crucial. The present retrospective multicenter study was conducted to investigate the clinical characteristics of Japanese patients with t(8;21) AML.

From January 2000 to December 2005, a total of 147 Japanese adult patients (15-years-old), who were newly diagnosed with de novo AML (FAB: M2) according to FAB classifications, were consecutively enrolled in nine collaborating hospitals. We retrospectively reviewed the medical records of these patients. These 147 patients included 46 patients with t(8;21) AML and 101 AML(M2) patients without t(8;21).

Diagnosis of t(8;21) AML was established based on chromosomal analysis (G-banding, n=45) and/or detection of RUNX1(AML1)/MTG8(ETO) fusion gene by real-time reverse transcription-polymerase chain reaction (n=16). Overall survival was calculated from diagnosis to death from any causes and event-free survival was defined as the time from diagnosis to the following events: first relapse of AML; treatment-failure; or death from any cause except leukemia. High-, standard- and low-dose cytarabine were defined as 2 g/m2/day, 100–200 mg/m2/day and 40 mg/m2/day, respectively. No patients received any other doses of cytarabine. Of the 46 patients with t(8;21), 4 were enrolled in the AML 202 study of the Japan Adult Leukemia Study Group.

Overall survival rate was calculated using the Kaplan-Meier product limit method. A log-rank test was applied to assess impact by the factor of interest when appropriate. Estimated survival was calculated as of January 31, 2007. Uni- and multivariate Cox proportional hazard models were applied to estimate the impact of potential prognostic factors. Factors associated with at least borderline significance (P<0.10) in univariate analyses were subjected to multivariate analysis using backward stepwise proportional-hazard modeling. Values of P<0.05 were considered statistically significant. Multivariate Cox proportional hazard models were used to determine the influence of age, sex and karyotype (with or without t(8;21)) on survival of all 147 patients. All analyses were conducted using STATA version 9.2 software (STATA, College Station, TX, USA).

Characteristics of AML patients with t(8;21) are shown in Table 1. Patients with t(8;21) (median age, 49.5 years; range, 18–86 years) were significantly younger than AML(M2) patients without t(8;21) (median age, 60 years; range 17–90 years; P<0.001). AML(M2) patients without t(8;21) included 57 men and 44 women. The median follow-up of surviving patients was 27.0 months (range, 0.2–82.6 months) after diagnosis.

Table 1 Characteristics and treatment of patients with t(8;21) AML

Twelve patients with t(8;21) AML died during follow-up at a median of 10.6 months (range, 3.1–80.1 months) after diagnosis due to primary disease (n=10), pneumonia (n=1) or sudden cardiac death (n=1). Overall survival rates at 3 years after diagnosis in patients with t(8;21) was 70% (95% confidence interval (CI), 51–83%). This rate was significantly better than that in AML (M2) patients without t(8;21) (overall survival at 3 years, 0.43 (95%CI, 0.32–0.54); log-rank test, P=0.005; Figure 1a). Among patients <60-years-old, overall survival rates of patients with t(8;21) AML and patients with non-t(8;21) AML(M2) were 71% (95%CI, 47–86%) and 58% (95%CI, 41–72%), respectively (log-rank test, P=0.28; Figure 1b). Event-free survival rate at 3 years in patients with t(8;21) was 54% (95%CI, 37–69%). Overall survival rates in patients with t(8;21) according to karyotype are shown in Figure 1c. No significant difference in overall survival (Figure 1c) or event-free survivals were noted between karyotypic groups (log-rank test, P=0.27 and P=0.51, respectively). There was not any significant association between presence of extramedullary involvement and additional karyotype abnormality (P=0.49).

Figure 1
figure1

Overall survival rates. Overall survival rates of the AML(M2) patient with or without t(8;21) were shown in (a). Overall survival rate at 3 years after diagnosis in patients with t(8;21) was 0.70 (95%CI, 0.51–0.83). Overall survival rate at 3 years after diagnosis in patients with non-t(8;21) AML(M2) was 0.43 (95%CI, 0.32–0.54) (a). A significant difference was identified between groups (log-rank test, P=0.005). Overall survival rates for AML(M2) patients <60-years-old were shown in (b). Overall survival rate at 3 years after diagnosis in patients with or without t(8;21) was 0.71 (95%CI, 0.47–0.86) and 0.58 (95%CI, 0.41–0.72), respectively. No significant difference was seen between groups (log-rank test, P=0.28) (b). Overall survival rates according to karyotype at diagnosis were shown in Panel c. Survival rates of the following karyotype groups are shown: (A) t(8;21)(q22;q22) without other karyotype abnormality; (B) t(8;21)(q22;q22) with loss of sex (Y) chromosome; (C) t(8;21)(q22;q22) with abnormal chromosome 9; D) t(8;21)(q22;q22) with 3 additional abnormalities; E) t(8;21)(q22;q22) with loss of X chromosome and F) other karyotype abnormalities. No significant difference was noted between groups (log-rank test, P=0.27) (c). Event-free survival rates with high- and standard-dose cytarabine were shown in (d). Event-free survival rates at 3 years after diagnosis in patients with consolidation therapy containing high- and standard-dose cytarabine were 57% (95%CI, 32–76%) and 64% (95%CI, 34–83%), respectively (log-rank test, P=0.69) The four patients who received the allogeneic stem cell transplantation in the first complete remission were excluded from the analysis (d). AML, acute myeloid leukemia; CI, confidence interval.

Of the 45 patients who received induction therapy, 36 and 5 patients achieved CR after first and second courses of chemotherapy, respectively (Table 1). CR rate was 91%.

Of the 40 patients who received induction therapy containing standard-dose cytarabine, 38 achieved CR. Among those, 21 patients received high-dose cytarabine-containing consolidation therapy. One of the 21 patients died in CR during consolidation therapy, due to infection. Event-free survival rates in patients with and without high-dose cytarabine were shown in Figure 1d.

In multivariate analysis, age and white blood cell count at diagnosis represented significant unfavorable predictors of overall survival. White blood cell count and lactate dehydrogenase level at diagnosis represented significant unfavorable predictors of event-free survival. (Table 2) Among 147 patients with AML (M2), presence of t(8;21) was not a significant predictor of survival (hazard ratio, 0.65; 95%CI 0.34–1.24; P=0.19) in multivariate analysis.

Table 2 Risk factors for overall and event-free survival in patients with t(8;21) AML

The present study demonstrated a more favorable survival rate for patients with t(8;21) AML in Japan than seen in recent studies conducted in western countries,4, 6, 7, 8 even though median age in the present study (49.5 years) was higher than those in recent studies (28–43 years).4, 6, 7, 8 Median white blood cell count and platelet count in the present study, which have been reported as predictors of survival in previous studies,4, 6, 7, 8 were consistent with those in previous studies. Differences in patient backgrounds between recent studies and ours are thus unlikely to have affected survival rates. These results indicate that t(8;21) AML in Japanese patients is associated with more favorable outcomes than seen in patients from western countries. Prognosis of t(8;21) AML may differ according to ethnicity, although statically analysis was not conducted. Further large-scale studies to investigate differences in clinical outcome among patients of various ethnicities thus appear warranted.

Interestingly, differences in overall survival between t(8;21) AML patients and AML(M2) without t(8;21) patients were unclear after adjusting for age (Figure 1b). One possible explanation is that AML (M2) in Japanese patients is associated with favorable outcomes. Another explanation is that favorable outcomes for t(8;21) AML are greatly related to low patient age. To date, information on clinical differences after adjusting for age between t(8;21) AML and AML(M2) without t(8;21) limited, and is worth investigating in future studies.

Additional karyotype abnormalities have been reported as an unfavorable prognostic factor for t(8;21) AML.1 The significance of these abnormalities may vary with ethnicity.4 In the present study, the prognostic impact of additional karyotype abnormalities (including loss of the sex chromosome and abnormal chromosome 9) was uncertain, consistent with a previous study from Japan.5 Additional karyotype abnormalities may not represent an important prognostic factor in Japanese patients. However, trisomy 4 still requires special consideration. All 3 Japanese patients with trisomy 4 in an earlier study died within 3 years.5 This additional karyotype warrants further investigation, since the present study did not include these patients.

No clinical impact of high-dose cytarabine consolidation therapy in Japanese t(8;21) AML patients was demonstrated in the present study, inconsistent with previous studies from western countries.1, 2 Efficacy of high-dose cytarabine may differ between patients from Japan and western countries. Since intensive chemotherapy such as high-dose cytarabine carries a risk of treatment-related morbidity and mortality, clinicians must carefully select eligible patients who would benefit from this regimen. Overall survival rate in patients with high-dose cytarabine was not inferior to that in patients who received standard or low-dose regimens (data not shown). Our results indicate that high-dose cytarabine consolidation chemotherapy is feasible in Japanese patients with t(8;21) AML and that investigation of efficacy by conducting a randomized trial in Japan is warranted.

Despite providing novel and useful information on t(8;21) AML in Japan, some issues remain to be discussed. First, the patients known to have a less good prognosis, such as those with additional trisomy 4 was not included in the present study. Second, the information on tyrosine kinase mutations in the patients with t(8;21) was not presented in the present study. The tyrosine kinase mutations among various ethnicities are require to investigate in future studies, since those could influence the prognosis. Furthermore, specific mutations often associated with t(8;21), such as N-Ras and Flt3 besides c-kit are also worth investigating. The last detailed information of AML(M2) patients without t(8;21), including white blood cell count and karyotype at diagnosis, and induction and consolidation treatment were not available in the present study. Those require to be investigated in future studies.

In summary, the clinical characteristics of t(8;21) AML might differ between patients from Japan and western countries. Clinicians should be alert to potential clinical differences among ethnicities. Further large-scale studies on differences in clinical characteristics among various ethnicities including Japanese patients are required.

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Acknowledgements

We thank all the staff and resident members of the participating institutions. A complete list of participating institutions appears in the Appendix.

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Correspondence to H Narimatsu.

Appendix

Appendix

This study was conducted at the following institutions: National Hospital Organization Nagoya Medical Center, Nagoya; Toyohashi Municipal Hospital, Toyohashi; Meitetsu Hospital, Nagoya; Fujita Health University Hospital, Toyoake; Komaki City Hospital, Komaki; Yokkaichi Municipal Hospital, Yokkaichi; Yamanashi Prefectural Central Hospital, Yamanashi; Okazaki City Hospital, Okazaki, Japan.

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Narimatsu, H., Yokozawa, T., Iida, H. et al. Clinical characteristics and outcomes in patients with t(8;21) acute myeloid leukemia in Japan. Leukemia 22, 428–432 (2008). https://doi.org/10.1038/sj.leu.2404905

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