| Acute myeloid leukemia(AML)with t(8;21)abnormality is one of the unique entities within the category “AML with recurrent genetic abnormalities” recognized by the World Health Organization classification.AML with t(8;21),also called CBFα-AML which with a frequency of about 7% in de novo adult AML,is considered as a favorable AML risk group based on their high remission rate and survival probabilities,but relapse still occur in 30%-40% of patients and only 40%-60% of patients with t(8;21)could be cured with standard high-dose cytarabine(HDAC)based regimens.It is very important to explore a new chemotherapy regimen which can improve the prognosis of CBFα-AML and analyze the risk factors correlated with relapse.Some researches demonstrated that fludarabine in combination with cytarabine and G-CSF(FLAG)was effective for primary resistant or relapsed AML with reducing the risk of relapse.Thus,whether consolidation therapy with fludarabine and cytarabine could improve the prognosis of CBFα-AML is worth to study.Numerous prognostic factors have been identified to be correlated with a high risk of relapse including patient’s age,hyperleucocytosis,additional cytogenetic aberrations,gene mutations such as c-KIT,and minimal residual disease(MRD).To date,the clinical significance of c-KIT mutations in CBFα-AML has been intensively studied,but the results are controversial.To evaluate whether fludarabine and cytarabine can improve the prognosis of CBFα-AML,a comparative analysis of fludarabine and cytarabine(FA)versus high dose cytarabine(HDAC)in consolidation treatment of CBFα-AML patients was conducted.Meanwhile,multivariate prognostic analysis was carried out to evaluate the prognostic factors.Purpose: To evaluate the effects of FA regimen versus HDAC regimen in consolidation treatment of CBFα-AML patients and the prognostic factors of CBFα-AML.Methods: Between September 2009 to May 2015,fifty patients aged 13-66 years with CBFα-AML were diagnosed in our institute.After one or two cycles of induction therapy,48 patients achieved complete remission(CR),1 with partial remission(PR)and 1 with non-remission(NR).5 cases(3 CR,1 PR and 1 NR cases)were excluded in the study due to abandoning further chemotherapy.Among the 45 patients with CR,23 cases were treated with FA(fludarabine 30mg/m2 d1-5,cytarabine 1.4g/m2 d1-5)and 22 cases were treated with HDAC(cytarabine 2g/m2/12 h for 6 doses).All patients received 4 courses of consolidation therapy.The median follow-up was 37.5 months(range,5.5-77.5 months).Clinical variables across groups were compared using the χ2 or a 2-sided Fisher exact test for categorical variables,and the nonparametric Mann-Whitney U test was applied for continuous variables.Probabilities for OS and DFS were calculated by the Kaplan-Meier method,and the log-rank test was used to assess differences between survival curves.Estimates of CIRs were calculated only for patients achieving CR,and Fine and Gray’s test was used to evaluate differences in relapse rates.Subdistribution hazard of relapse(SHR)and HR were both given with 95% confidence interval(CI).For multivariate analysis of prognostic factors,Cox proportional hazards regression models were constructed for OS and DFS,and proportional hazards assumption was graphically checked,multivariable models using Gray’s method were constructed for CIR.CR rates and MRD response across treatment groups were compared using Fisher’s exact test.All statistical analyses were performed using R version 3.1.3.P values below 0.05 were considered to be significant.Results:1.The basic clinical characteristics of patients in FA arm and HDAC arm: The median age of two groups were 44 years and 37.5 years respectively;male percent: 52.17%,54.55%.FAB subtype AML-M2: 16 and 15 cases;AML-M4: 5 and 5 cases;AML-M5: 2 and 2 cases.Additional cytogenetic abnormality loss of Y: 7 and 7 cases;trisomy 4: 1 and 0 cases;trisomy 8: 0 and 1 cases;loss of X: 1 and 1 cases;normal cytogenetic: 2 and 0 cases.Mutated genes c-KIT mutation: 6 and 4 cases;CEBPα: 1 and 2 cases.CD56 expression: 16 and 16 cases.There were no significant differences between the two groups.(P>0.05)2.Clinical outcomes: At 3 years,OS from CR was estimated at 91.1%(95%CI,80%-100%)in FA arm,which was significantly higher than 48.4%(95%CI,30%-78%)in HDAC arm,P=0.0147 by the log-rank test.RFS was estimated at 81.73%(95%CI,67%-99.7%)in FA arm,which was significantly higher than 50.73%(95%CI,32.8%-78.5%)in HDAC arm,P=0.0432 by the log-rank test.CIR was estimated at 18.27%(95%CI,5.473%-36.976%)in FA arm and 47.39%(95%CI,24.47%-67.30%)in HDAC respectively.Although the difference of CIR between the two treatment arms was not significant,there was a markedly trend of decreased CIR in FA arm(SHR: 0.339,95%CI [0.109,1.06]),P=0.0546 by the Fine and Gray’s test.3.Minimal residual disease before the second consolidation(MRD2)reduction ≥3logs was presented in 29 cases,of which 4 cases relapsed and 25 cases didn’t relapse;8 cases with MRD2 reduction <3logs,of which 5 cases relapsed and 3 cases didn’t relapse.The difference was significant(P=0.0115).The results demonstrated that the status of MRD2 was correlated with relapse.Patients with MRD2 reduction ≥3logs had lower possibility of relapse.MRD reduction before the first,third and fourth consolidation(MRD1,MRD3,MRD4)was not correlated with relapse.4.Univariate prognostic analysis: factors with P values below 0.1 were defined as probable factors.(1)Probable factors correlated with subdistribution hazard of relapse(SHR):(1)four factors correlated with higher SHR:c-KIT mutations(SHR 5.39 [95%CI,1.94-15],P=0.0013),additional cytogenetic abnormalities(lose of Y chromosome)(SHR 2.74[95%CI,0.991-7.6],P=0.052),higher WBC counts(SHR 2.38 [95%CI,0.913-6.18],P=0.076),higher bone marrow blasts(%)(SHR 1.03 [95%CI,1-1.05],P=0.041).(2)Three factors were identified to be correlated with decreasing the relapse risk:FA treatment(SHR 0.339 [95%CI,0.109-1.06],P=0.063),female patients(SHR 0.265 [95%CI,0.0704-1],P=0.05),MRD2 reduction ≥ 3logs(SHR 0.125 [95% CI,0.0369-0.424],P=0.00085).(2)Probable factors correlated with RFS:(1)Three factors correlated with higher RFS:MRD2 reduction ≥ 3logs(HR 0.126 [95%CI,0.033-0.475],P=0.0022),female patients(HR 0.251 [95%CI,0.070-0.905],P=0.0347),FA treatment(HR 0.323 [95%CI,0.101-1.032],P=0.0565).(2)Five factors with a decreasing RFS:higher WBC counts(HR 2.774 [95%CI,0.954-8.068],P=0.0610),higher bone marrow blasts(%)(HR 1.027 [95%CI,1.001-1.052],P=0.0402),higher LDH level(HR 1.001 [95%CI,1.000-1.001],P=0.0379),additional cytogenetic abnormalities(lose of Y chromosome)(HR 3.039 [95%CI,1.060-8.718],P=0.0387),c-KIT mutations(HR 5.465 [95%CI,1.876-15.920],P=0.0018).(3)Probable factors correlated with OS from CR:(1)Two factors correlated with higher OS: MRD2 reduction ≥ 3logs(HR 0.134 [95%CI,0.032-0.567],P=0.0063),FA treatment(HR 0.0565 [95%CI,0.041-0.846],P=0.0296).(2)Two factors with a decreasing OS: higher WBC counts(HR 5.157 [95%CI,1.596-16.670],P= 0.0061),higher LDH level(HR 1.001 [95%CI,1.000-1.001],P=0.0778).5.Multivariate prognostic analysis:(1)Based on multivariate analysis,treatment regimen(FA vs HDAC),MRD2 status(reduction ≥ 3logs vs reduction < 3logs)and c-KIT gene status(with mutation vs without mutation)were the independent prognostic factors for SHR.The SHR was 0.17(95%CI,0.444-0.647;P=0.0094)for FA treatment,0.166(95%CI,0.0410-0.672;P=0.012)for MRD2 reduction ≥ 3logs and 12.368(95%CI,3.9332-38.894;P=0.000017)for c-KIT gene mutations.(2)Multivariate analysis demonstrated that treatment regimen,MRD2 status and c-KIT gene status were independent prognostic factors for HR of RFS as similar with SHR.The HR for RFS was 0.108(95%CI,0.017-0.681;P=0.0179)for FA treatment,0.140(95%CI,0.025-0.783;P=0.0252)for MRD2 reduction ≥ 3logs and 18.806(95%CI,3.277-107.938;P=0.001)for c-KIT gene mutations.(3)Three factors of treatment regimen,MRD2 status and WBC counts were identified as independent prognostic factors for OS from CR.The HR for OS was 0.205(95%CI,0.039-1.075;P=0.069)for FA treatment,0.067(95%CI,0.010-0.424;P=0.0041)for MRD2 reduction ≥ 3logs and 7.833(95%CI,1.620-37.866;P=0.0105)for higher WBC counts.6.Exploratory subgroup analysis:(1)The patients with c-KIT unmutated and MRD2 reduction≥ 3 logs had a high OS of 84.3%(95%CI,69.1%-100%)and low CIR of 4.792%(95%CI,0.3%-20.3%);while the patients with c-KIT mutation and MRD2 reduction≥ 3 logs had a high CIR of 70%(95%CI,1.1%-97.2%),although the OS was also high of 80%(95%CI,51.6%-100%).(2)None of patients in FA arm without c-KIT mutation relapsed and OS of these patients was 100%(95%CI,100%-100%),which was higher than 51.4%(95%CI,31.8%-83.2%)in HDAC arm,P=0.004;while the CIR of patients in FA arm was 0(95%CI,0-0),which was lower than 40.28%(95%CI,17.21%-62.5%)in HDAC arm,P=0.006053.Meanwhile,the RFS of patients without c-KIT mutation in FA arm was 100%(95%CI,100%-100%),which was higher than 57.8%(95%CI,38.1%-87.6%)in HDAC arm,P=0.0048.(3)A high relapse of 66.67%(95%CI,12.54%-92.39%)was presented in FA arm with c-KIT mutation,although the OS was 66.7%(95%CI,37.9%-100%).7.Toxicity profiles: the intensity of myelosuppression,the incidence of liver dysfunction and the frequency of invasive fungal disease were similar between two treatment arms.(P>0.05)Conclusion: 1.FA consolidation treatment significantly improved OS and RFS of CBFα-AML patients compared with HDAC,especially for patients without c-KIT mutation.2.The status of MRD2 was correlated with relapse.Patients with MRD2 reduction ≥3logs had lower possibility of relapse.3.MRD2 reduction≥ 3logs and FA treatment were favorable factors for CBFα-AML patients,while c-KIT mutation was a risk factor for CBFα-AML patients.4.A newly diagnosed CBFα-AML patient should receive four courses of FA consolidation if the patient doesn’t harbor a mutated c-KIT gene,while a patient harbors a mutated c-KIT gene,allogeneic hematopoietic stem cell transplantation should be considered at early time. |
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