Post-remission therapy of adult acute myeloid leukemia: high dose cytosine-arabinoside versus other consolidation regimens/Konsolidaciona terapija akutne mijeloidne leukemije: visoke doze citozinarabinozida naspram drugih konsolidacionih rezima sa citozin-arabinozidom.
Acute myeloid leukemia (AML) is the most common leukemia affecting adults. Approximately 300,000 patients worldwide are diagnosed annually with AML . Modern therapy makes it possible for 60-80% patients with de novo AML to achieve complete remission [1-3]. However, most of them will relapse within six months to a year without additional post-remission therapy [4, 5]. Thus, the optimal post-remission therapy is still the major challenge.
A number of studies have suggested that the increased intensity of post-remission therapy prolongs remission duration and leads to superior survival. The Cancer and Leukemia Group B (CALGB) conducted a study in order to assess whether there was a dose-effect correlation of cytosine-arabinoside. The study showed that high dose cytosine-arabinoside (HDAC) (3 g/[m.sup.2]) given in four courses resulted in the 2uperior survival compared to a lower dose (0.4 g/[m.sup.2] and 1 g/[m.sup.2]), especially among the patients younger than 60 years and the patients with core binding factors (t(8; 21)(q22; q22j or inv(16)) . On the other hand, the American Intergroup 1998 study, where HDAC was given as a single course, yielded similar results . Thus, the questions such as the optimal dose and number of courses still remain unanswered. HDAC can cause cerebral and gastroin testinal lesions, dermatitis, conjunctivitis, liver lesion and acute lung failure [4, 8, 9].
The objective of this study was to compare the survival rate and the relapse rate among the patients who received HDAC during consolidation therapy and among the patients who did not receive HDAC during consolidation therapy. Material and Methods
Patients. The patients were divided into the study and control group. The study group consisted of the patients hospitalized at the Department of Hematology from July 2001 to May 2010. The control group consisted of the patients hospitalized at the Department of Hematology from November 1993 to December 2001. In addition, a gender- and age-matched group was formed of randomly selected patients from the study group in order to achieve greater comparability with the control historical group. The inclusion criteria were as follows: age 18 to 60, de novo AML according to French-American-British (FAB) classification  (Table 1) (excluding acute promyelocytic leukemia M3), achieving complete remission (CR). The patients with incomplete data were excluded (Table 2).
Treatment protocol. After being diagnosed with AML, all patients were treated with identical induction treatment. Post-remission therapy differed in the study and the control historical group, as detailed in Figure 1.
Assessment of response. The response to treatment (CR, relapse) and outcome (survival) was assessed according to European Leukaemia Net .
Statistical analysis. The following descriptive statistical methods were used for statistical analysis: Fisher's exact test and [x.sup.2] for categorical variables, the Shapiro-Wilk W test to determine the type of distribution of data and the Mann-Whitney test in the case of continuous data.
Survival analyses were done by the Kaplan-Meier method. The survival curves were compared by the log-rank test and the Cox proportional hazards model was used to analyze the effect of prognostic variables on survivals. Statistica 9.1 program was used for the statistical analysis.
Patients' characteristics The study group consisted of 39 patients with median age 45 years (ranging from 18 to 55 years). The control group included 20 patients with median age 48 years (ranging from 24 to 60 years). The age-matched group was formed of 20 patients randomly selected by computer from the study group, their median age being 46 years (ranging from 27 to 54 years). The patients' characteristics on admission are shown in Table 2. There were no significant differences in the patients' characteristics either between the study and the control historical group or between the age-matched and control historical group.
Survival, complete remission and relapse. By the time of evaluation, the mean follow up period in the study group was 29 months (ranging from 6.5 to 100 months) and in the control group it was 17 months (ranging from 5 to 209 months). The median survival in the study group was 37.6 months versus 17 months in the control group (the log-rank test, p = 0.003), as showed in Figure 2A. The median survival in the matched group was 34.5 months, which differed statistically from the control group. According to the log-rank test p = 0.003, CR after the first induction course was achieved by 54.6% of patients from the study group and 30% of patients from the control group (Yates corrected [x.sup.2], p= 0.07). The rate of relapse in the study group was 70.5% versus 90 % in the control group, which resulted in a significant difference according to the [x.sup.2] test (p= 0.02).
Factors predictive for survival. The log-rank test revealed a significant difference (p=0.006) when comparing survival for M4 and M1 subgroup, including the study and control historical group; the median survival time being 69.3 months and 11 months for M4 and M1 subgroup, respectively. There was also a significant difference (the log rank, p=0.011) comparing the survival between M4 and M0 subgroup (the median survival time was 16 months), M2 and M4 subgroup (p = 0.02), M4 and M5 subgroup (p = 0.02), but not when comparing the survival between other FAB subgroups. The median survival time in M2 subgroup was 20 months. The median survival for M0, M6 and M7 subgroups was not determined because of a small number of patients. The comparison of survival in M1, M2, M4 and M5 subgroups is shown in Figure 2B.
The comparison of survival in M2 and M4 subgroup together with the other FAB subgroups, in the study group alone, resulted in a significant difference in the survival (the log-rank, p = 0.014), the median survival time for M2 and M4 subgroup being 73 months and 28 months for all other FAB subgroups together, as shown in Figure 2C. The same comparison in the control historical group did not show a significant difference.
The median survival rate resulting from the comparison of the study and control group together was significantly higher (the log-rank test, p = 0.016) in the patients who achieved CR after the first induction course (39 months) than in the patients who achieved CR after two or more induction courses (20 months), which is shown in Figure 2D. If the same comparison was made within the groups themselves, no significant difference would be found.
Baseline hematological characteristics--median white blood cells, median platelets and median hemoglobin were not predictive of survival (the log-rank test). By using Cox logistic regression model for all patients and by examining consolidation treatment (HDAC versus other treatment), the affiliation to M2 and M4 subgroup versus other FAB subgroups and the number of induction courses to CR, all parameters emerged as significant variables affecting the survival, consolidation treatment (p=0.004), affiliation to M2 and M4 subgroup (p=0.017) and number of induction courses to CR (p=0.031). The application of Cox logistic regression model within the study group among the parameters tested (the affiliation to M2 and M4 subgroup versus other FAB subgroups and the number of induction courses to CR) resulted in a significant impact on the survival (p=0.02), whereas only the affiliation to M2 and M4 subgroups (p=0.018) seemed to be an independent prognostic factor.
AML responses to therapy are still unsatisfactory, the impediments most frequently being disease resistance, prolonged and recurrent infections and bleeding, as well as morbidity and mortality caused by the treatment itself [11, 12]. The need for any form of post-remission therapy was established a long time ago because patients without one would relapse within a year [4, 5]. Consolidation therapy is a standard treatment, whereas alternative treatments include allogeneic bone marrow transplantation, autologous bone marrow transplantation and maintenance therapy. A number of studies [6, 13-15] suggest that the increased intensity of post-remission chemotherapy has a positive effect--both on the survival and prolongation of CR in adults younger than 60 years. A particularly attractive candidate to be intensified is cytosine-arabinoside.
The results of our study have shown that HDAC can indeed prolong the survival and reduce the incidence of relapse compared to the patients who received another form of consolidation therapy. Our results are consistent with the results of previously published randomized and nonrandomized studies [4, 6, 13-15]. However, it should be mentioned that the longest follow-up of patients in the control group was 209 months, as opposed to the longest follow-up in the study group of 100 months. Also, it should not be ignored that the study group patients received one or two more cycles of consolidation more than the patients in the control group. They received two cycles of HDAC, which is in accordance with the recommendations of the National Cancer Center Network .
The most favorable prognostic subgroups of AML according to the literature  are M2, M3 and M4; however, it has not been confirmed so far [11,18,19]. According to the results of our study on the study and control group patients together, as well as on the patients form the study group itself, the superior survival was found within M4 and M2 subgroup. Therefore, it can be concluded that only the patients from M2 and M4 subgroup benefit from treatment with HDAC.
The karyotype is the strongest predictive factor for the response to induction therapy and for the survival [1, 3, 5]. A favorable outcome, primarily in the patients from M4 and M2 subgroup, can be explained by the fact that these subgroups commonly experienced cytogenetic changes--t (8; 21) in M2 and inv (16) in M4 Eo--which carry fa vorable prognosis [16, 20]. The results of CALGB 8461 study demonstrated that the median survival was 7.6 years in the patients with favorable karyotype compared to the median survival in the patients with intermediate (1.3 years) and adverse (0.5 years) cytogenetic abnormalities . In our study we did not have data on karyotype for all the patients, thus this parameter was not analyzed.
However, the largest subgroup of AML patients (~40%) has no identifiable cytogenetic abnormalities [3,5,19,21]. In this subgroup, molecular markers are the most important prognostic factors--mutations in the nucleophosmin (NPM1), CCAAT/enhancer binding protein (encoded by the CEBPA gene) and FMS-like tyrosine kinase 3 (FLT3) genes . Mutations of NPM1 and CEBPA gene are associated with a higher CR rate and the better overall survival, if not combined with FLT3 gene mutation [3,5,22]. On the other hand FLT3 gene mutations, alone or combined, lead to inferior outcome [3,5,21]. C-Kit mutation in patients with good cytogenetic disorders also carries the adverse prognostic significance . NPM mutations mostly occur in M4 subgroup , CEPBA mutations are mostly found in M1 and M2 subgroup , whereas FLT3 mutations are most frequent in M0 and M5 subgroup . We assumed that the favorable outcome of consolidation therapy with HDAC in the M2 and M4 subgroup in our study was partly achieved in the patients with favorable genetic and molecular mutations.
In our study, as in the study performed by Zittuon et al. , and by Popovic , the initial factor with the prognostic value was the number of induction courses to CR. However, in the multivariate analysis of the study group where we observed one versus two or more induction courses and the affiliation to M2 and M4 subgroup versus other FAB subgroups, only the affiliation to M2 and M4 FAB subgroup retained the independent prognostic significance. Therefore, we suppose that the patients from M2 and M4 subgroup achieve a high CR rate after one induction course as a result of associated favorable cytogenetic and molecular aberrations.
AML is a heterogeneous group of disorders where post-remission treatment should be based on the prognostic factors, primarily on karyotype. A reasonable choice for the patients with favorable cytogenetic disorders is consolidation therapy with repetitive cycles of HDAC. For the patients with adverse cytogenetic disorders, a superior outcome is achieved with transplantation . The approach to treatment with intermediate prognosis is not unique, but there is clinical evidence suggesting that transplantation is indicated in the first remission in case of FLT3-ITD mutation, and in case of relapse with isolated NPM1 or CEBPA mutations .
This study demonstrates that high dose cytosine-arabinoside used for consolidation therapy results in a higher survival rate and a lower rate of relapse compared to consolidation therapy without high dose cytosine-arabinoside. However, high dose cytosine-arabinoside showed a significant benefit only to the patients in M2 and M4 French-American-British subgroup. In addition to the cytogenetic analysis, which is neces sary during the diagnostic evaluation, the molecular genetic analysis is to be done in case of normal karyotype and then, on the basis of results, to opt for post-remission therapy in accordance with conventional prognostic factors. Further investigations on a large group of patients, which would include cytogenetic and molecular analyses, especially FMS-like tyrosine kinase 3 gene and nucleophosmin mutations, are needed in order to evaluate favorable effects of high-dose cytosin-arabinoside on the survival.
Abbreviations AML -acute myeloid leukemia CALGB -Cancer and Leukemia Group B HDAC -high dose cytosine-arabinoside FAB -French-American-British CR -complete remission NPM -nucelophosmin M3 -acute promyelocit FLT3 -FMS-like tyrosine kinase 3
Rad je primljen 9. VI 2013.
Recenziran 20. XI 2013.
Prihvacen za stampu 14. I 2014.
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Vanja ZEREMSKI and Aleksandar SAVIC
Clinical Center of Vojvodina, Novi Sad, Serbia Department of Hematology Faculty of Medicine, University of Novi Sad
Corresponding Author: Dr Vanja Zeremski, Klinicki centar Vojvodine, Klinika za hematologiju, 21000 Novi Sad, Hajduk Veljkova 1-7, E-mail: firstname.lastname@example.org
Table 1. The French-American-British (FAB) classification of AML Tabela 1. Francusko-americko-britanska klasifikacija M0 Acute myeloblastic leukemia, minimally differentiated M1 Acute myeloblastic leukemia without maturation M2 Acute myeloblastic leukemia with maturation M3 Acute promyelocytic leukemia M4 Acute myelomonocytic leukemia M4eos Acute myelomonocytic leukemia with eosinophilia M5 Acute monocytic leukemia M6 Acute erythroid leukemia M7 Acute megakaryoblastic leukemia Table 2. Initial patient characteristics Tabela 2. Inicijalne karakteristike bolesnika Study group Control group Studijska grupa Kontrolna grupa No. of patients/Broj pacijenata 39 20 Sex/Pol Men (%)/Muskarci 53,18 55 Women (%)/Zene 46,82 45 Age/Starost Median/Srednja vrednost 45 48 Range/Raspon 18-55 24-60 FAB * M0 5 1 M1 3 5 M2 11 8 M4 15 5 M5 4 1 M6 1 0 M7 0 0 WBC ([dagger]) Leukociti Median/Srednja vrednost 20,25 7,85 Range/Raspon 1,07-197 1,2-50,64 Eritrociti/RBC ([double dagger]) Median/Srednja vrednost 2,83 2,75 Range/Raspon 1,19-5,65 2,04-3,87 Hemoglobin Median 91,5 88,15 Srednja vrednost Range Raspon 47,6-170 57-127 Hematokrit Hematocrit Median 0,26 0,24 Srednja vrednost Range Raspon 0,13-0,51 0,17-0,38 Platelets Trombociti Median 70,7 65 Srednja vrednost Range Raspon 13-274 20,2-210 ECOG 0-1 17 7 [greater than or equal to] 2 14 7 Unknown/Nepoznat 8 6 HCTCI 0 30 10 1-2 6 8 [greater than or equal to] 3 3 1 Unknown n 1 Nepoznat 0 1 Matched group Uporedna grupa No. of patients/Broj pacijenata 20 Sex/Pol Men (%)/Muskarci 50 Women (%)/Zene 50 Age/Starost Median/Srednja vrednost 46 Range/Raspon 27-54 FAB * M0 2 M1 1 M2 4 M4 10 M5 2 M6 1 M7 0 WBC ([dagger]) Leukociti Median/Srednja vrednost 11,9 Range/Raspon 1,43-75,7 Eritrociti/RBC ([double dagger]) Median/Srednja vrednost 2,94 Range/Raspon 1,19-3,57 Hemoglobin Median 92,9 Srednja vrednost Range Raspon 47,6-117 Hematokrit Hematocrit Median 0,27 Srednja vrednost Range Raspon 0,13-0,33 Platelets Trombociti Median 67 Srednja vrednost Range Raspon 13-274 ECOG 0-1 9 [greater than or equal to] 2 8 Unknown/Nepoznat 3 HCTCI 0 13 1-2 4 [greater than or equal to] 3 3 Unknown n Nepoznat 0 * French-American-British; ([dagger]) White blood cells; ([[double dagger]]) Red blood cells
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|Title Annotation:||Original study/Originalni naucni rad|
|Author:||Zeremski, Vanja; Savic, Aleksandar|
|Date:||Mar 1, 2014|
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