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Prognostic significance of recurrent additional chromosomal abnormalities in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia
Accepted Manuscript Title: Prognostic Significance of Recurrent Additional Chromosomal Abnormalities in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Author: Chang Ahn Seol, Young-Uk Cho, Seongsoo Jang, Chan-Jeoung Park, Jung-Hee Lee, Je-Hwan Lee, Kyoo Hyung Lee, Eul-Ju Seo PII: DOI: Reference:
S2210-7762(17)30080-7 http://dx.doi.org/doi: 10.1016/j.cancergen.2017.06.001 CGEN 531
To appear in:
Cancer Genetics
Received date: Revised date: Accepted date:
7-3-2017 19-5-2017 7-6-2017
Please cite this article as: Chang Ahn Seol, Young-Uk Cho, Seongsoo Jang, Chan-Jeoung Park, Jung-Hee Lee, Je-Hwan Lee, Kyoo Hyung Lee, Eul-Ju Seo, Prognostic Significance of Recurrent Additional Chromosomal Abnormalities in Adult Patients with Philadelphia ChromosomePositive Acute Lymphoblastic Leukemia, Cancer Genetics (2017), http://dx.doi.org/doi: 10.1016/j.cancergen.2017.06.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Original Article
Prognostic Significance of Recurrent Additional Chromosomal Abnormalities in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
a
a
a
a
b
Chang Ahn Seol , Young-Uk Cho , Seongsoo Jang , Chan-Jeoung Park , Jung-Hee Lee , Jeb
b
a,
Hwan Lee , Kyoo Hyung Lee , Eul-Ju Seo * a
Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical
Center, Seoul, Korea;
b
Department of Internal Medicine, University of Ulsan College of Medicine and
Asan Medical Center, Seoul, Korea
* Corresponding author: Eul-Ju Seo, M.D. Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: +82 2 3010 4507, Fax: +82 2 478 0884, E-mail: [email protected]
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Abstract In Philadelphia (Ph)
chromosome-positive acute
lymphoblastic
leukemia (ALL), additional
chromosomal abnormalities (ACAs) are frequently observed. We investigated the cytogenetic characteristics and prognostic significance of ACAs in Ph-positive ALL. We reviewed the clinical data and bone marrow cytogenetic findings of 122 adult Ph-positive ALL patients. The ACAs were examined for partial or whole chromosomal gains or losses, and structural aberrations. The overall survival (OS) and disease-free survival (DFS) of patients who received hematopoietic cell transplantation were compared between the isolated Ph group and ACA group. ACAs were present in 73.0% of all patients. The recurrent ACAs were extra Ph (24.7%), 9/9p loss (20.2%), and 7/7p loss (19.1%). Complex karyotype was found in 28.1% of patients in the ACA group. Younger patients (1930 years) in the ACA group showed the highest frequency of extra Ph (54%) compared to other age groups. The OS in the ACA group was significantly shorter than in the isolated Ph group. The presence of an extra Ph chromosome or 9/9p loss was significantly associated with shorter OS and DFS, whereas 7/7p loss and complex karyotype were not associated with poorer prognosis. We suggest that subclassification of ACAs could be applied to prognostic investigation of Ph-positive ALL. Keywords Acute lymphoblastic leukemia, Philadelphia chromosome-positive, additional chromosomal abnormality, prognosis
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Introduction The Philadelphia (Ph) chromosome is the most common chromosomal aberration in adult acute lymphoblastic leukemia (ALL) and is associated with an unfavorable prognosis. The Ph chromosome is observed in 15-30% of adult ALL patients, compared to 2-4% of children with ALL; the frequency of the Ph chromosome can approach 50% in 40-50-year-old ALL patients [1-6]. Additional chromosomal abnormalities (ACAs) are frequently observed in Ph-positive ALL patients, compared to chronic myelogenous leukemia patients in the chronic phase [7,8]. In previous studies, the frequency of ACAs in Ph-positive adult ALL patients was 42-71% [1,9-13]. However, the prognostic impact of ACAs has not been established and controversies regarding the impact of ACAs remain. In several reports, ACAs in Ph-positive ALL patients were not associated with a worse prognosis compared to those in isolated Ph-positive ALL patients [1,10,13]. In other studies, Ph-positive ALL patients with ACAs showed a worse prognosis compared to the isolated Ph-positive ALL patients [9,11,12,14,15]. Whether recurrent ACAs such as 7/7p loss are associated with poor prognosis is debatable [9,12]. Studies on ACAs in Ph-positive ALL patients, especially in the post tyrosine kinase inhibitor (TKI) era, are lacking [9,14]. In this study, we retrospectively investigated the frequency and prognostic impact of ACAs in Ph-positive adult ALL patients from a single institute. The investigation was focused on the analysis of recurrent abnormalities in the ACAs and the prognostic significance of the recurrent ACAs in the patients who received hematopoietic cell transplantation (HCT).
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Materials and Methods Patients The subjects of this study comprised 122 patients diagnosed with Ph chromosome-positive ALL between 2000 and 2015 at the Asan Medical Center, Seoul, Korea. The diagnosis of Ph-positive ALL was performed according to the WHO classification of tumors of hematopoietic and lymphoid tissues [16]. Subjects were required to be 19 years of age or older at the time of diagnosis for inclusion in the study. The median age of the subjects was 49.5 years (19-80). We retrospectively reviewed the clinical data, laboratory findings, and cytogenetic findings of the bone marrow (BM) aspirate from the medical records of each subject. The clinical and laboratory findings included age, sex, complete blood cell counts and blast percentage in peripheral blood (PB), serum lactate dehydrogenase (LDH) level, results of immunophenotypic analysis, major or minor BCR-ABL1 fusion transcript, and treatment modalities such as chemotherapy and HCT. The subjects were assigned to the isolated-Ph group or the ACA group. The clinical and laboratory findings were compared between the 2 groups. This study was approved by the Institutional Review Board of the Asan Medical Center, Seoul, Korea. Treatment The induction chemotherapy comprised vincristine, daunorubicin, TKI (imatinib or dasatinib), and steroid
treatment
(prednisolone,
methyl
prednisolone,
or
dexamethasone).
Consolidation
chemotherapy comprised cyclophosphamide, cytosine arabinoside, high-dose methotrexate, TKI, and steroid treatment. Central nervous system prophylaxis was performed by intrathecal methotrexate injection. For the patients who received HCT after chemotherapy including TKI (n=74), the conditioning
regimen
comprised
busulfan,
fludarabine,
methotrexate,
and
antithymocyte
immunoglobulin. The study subjects included the patients who received only chemotherapy including TKI (n=34), the patients who received only chemotherapy without TKI (n=7), and the patients who did not receive chemotherapy (n=7). Complete remission (CR) was defined according to the ALL response criteria of the National Comprehensive Cancer Network [17]. Relapse was defined as reappearance of lymphoblasts accounting for more than 5% of the nucleated cells in BM, or appearance of extramedullary leukemia, after CR. Cytogenetic analysis BM cells were cultured with RPMI-1640 working medium and fetal bovine serum for 24 and 48 hours in a 37°C 5% CO2 incubator. Using colcemid and 0.075 M potassium chloride solution, the metaphase 4
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cells were harvested. The metaphase cells were stained by GTL-banding technique. At least 20 metaphase cells were analyzed in each patient. The results of chromosomal analysis were described according to the International System for Human Cytogenetic Nomenclature [18]. The ACAs from the karyotype descriptions were examined for partial or whole chromosomal gains or losses, and structural aberrations. A complex karyotype was defined as having equal to or more than 4 independent chromosomal aberrations. The type and frequency of recurrent ACAs were investigated in the patients in the ACA group. The patients were divided into 5 age groups (19-30 years, 31-40 years, 41-50 years, 51-60 years and >60 years group) and the frequencies of ACAs were also investigated in each age group. Statistical analysis The quantitative data were presented as medians (ranges). The comparison of the clinical and laboratory data between the ACA group and the isolated-Ph group was performed by Mann Whitney U-test or Pearson’s Chi-square test. The comparisons of the frequencies of recurrent ACAs in the age groups were performed by Pearson’s Chi-square test or Fisher’s exact test. Overall survival (OS) was defined as time from date of diagnosis to time of death for any reason. The disease-free survival (DFS) was defined as time from date of CR to date of relapse or death for any reason. The 5-year survival rate was presented as an estimated rate ± standard error and the median survival was presented as an estimated survival ± standard error. The OS and DFS in the patients who received HCT were analyzed by the Kaplan-Meier method, and the outcomes were compared between the ACA group and the isolated Ph group by the log-rank test. The OS and DFS in the patients who received only chemotherapy including TKI were also compared between the ACA group and the isolated Ph group. Cox proportional hazard models for multivariate analysis were used to investigate hazard ratios of recurrent ACAs for the total patients. SPSS 19.0 (IBM, Chicago, USA) was used for the statistical analysis and a p-value of <0.05 was considered statistically significant.
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Results Clinical and laboratory data The clinical and laboratory findings are summarized in Table 1. ACAs were present in 73.0% of total patients with Ph-chromosome positive ALL. The incidence of patients with ACAs was not significantly different by sex or age. The median age and male proportion were 53 years and 45.5% in the isolated Ph group, compared to 49 years and 51.7% in the ACA group. The complete blood cell counts were not significantly different between the isolated Ph group and the ACA group. The blast counts in PB, serum LDH level, the immunophenotype of BM flow cytometry, and the proportion of major and minor BCR-ABL1 transcripts in the ACA group were compared with the results in the isolated Ph group; no statistically significant difference was found. The proportion of patients who received HCT after chemotherapy including TKI in the isolated Ph group and in the ACA group was 57.6% and 61.8%, respectively (p=0.682). Cytogenetic analysis of ACAs Based on the cytogenetic results of the ACA group, the frequencies of the ploidy levels of the karyotypes and recurrent ACAs are presented in Figure 1. According to the ploidy levels of the karyotypes, pseudodiploidy was the most common, and found in 41.6% of the patients in the ACA group. Hypodiploidy of 45 chromosomes was found in 21.3% of patients, and hyperdiploidy of 47 to 50 chromosomes was found in 24.7% of the patients in the ACA group. The ACAs included recurrent types of ACAs, such as extra Ph (24.7%), loss of 9/9p (20.2%), and loss of 7/7p (19.1%). Complex karyotype was present in 28.1% of the patients in the ACA group. The distributions of numerical and structural aberrations are presented across all chromosomes in Figure 2. Monosomy 7 and monosomy 9 were frequently observed as numerical aberrations (Figure 2A). Moreover, 7p, 9p and 22q abnormalities were frequently observed as structural aberrations (Figure 2B). Frequent 22q abnormalities were due to extra Ph. The frequency of ACAs by age group did not differ significantly; the frequency was 81% (n=16), 72% (n=18), 77% (n=30), 62% (n=29), and 76% (n=29) in the 19-30-year, 31-40-year, 41-50year, 51-60-year, and >60-year age groups, respectively. The frequencies of recurrent ACAs, such as extra Ph, loss of 9/9p, loss of 7/7p, and complex karyotype in the patients with ACAs, by age group, are presented in Figure 3. In the 19-30-year-age group, the frequency of extra Ph (54%) was significantly higher than in other age groups (p=0.008). Complex karyotypes were frequently observed 6
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across all the age categories in the ACA group. They comprised structural aberrations such as unbalanced translocations (88%) and balanced translocations (16%) and numerical aberrations such as trisomies (36%) and monosomies (44%) and the distributions of those aberrations in complex karyotypes were not different across the age categories. Prognostic analysis of ACAs For the patients who received HCT (n=74), the comparison of OS and DFS was performed between the ACA group (n=55) and the isolated Ph group (n=19). The median follow-up time after diagnosis in the ACA group was 31 months (4.8-166 months), compared to 53 months (12-169 months) in the isolated Ph group. The 5-year OS rate of 40.5±7.7% in the ACA group was significantly lower than the 5-year OS rate of 76.5±10.3% in the isolated Ph group (p=0.024). The 5-year DFS rate of 45.9±8.5% in the ACA group showed a low tendency compared to the 5-year DFS rate of 61.1±12.6% in the isolated Ph group (p=0.195) (Figure 4). For the patients who only received chemotherapy including TKI (n=34), the comparison of OS and DFS was also performed between the ACA group (n=24) and the isolated Ph group (n=10). The median OS was 11.5±3.1 months in the ACA group compared to 25.3±15.8 months in the isolated Ph group (p=0.663) and the median DFS was 17.6±10.0 months in the ACA group compared to 22.8±1.5 months in the isolated Ph group (p=0.985). For the patients who received HCT (n=74), we analyzed the prognostic impact of recurrent ACAs, such as extra Ph, loss of 9/9p, loss of 7/7p, and complex karyotype. The 5-year OS and DFS rates of patients with extra Ph in the ACA group were 31.6±13.2% and 34.1±14.9%, respectively, and the Kaplan-Meier curves showed a tendency toward lower OS and DFS rates than in the isolated Ph group (p=0.014 and p=0.072, respectively). The 5-year OS and DFS rates of patients with loss of 9/9p in the ACA group were 44.0%±14.3 and 34.3±15.3%, respectively, and the Kaplan-Meier curves showed a tendency toward lower OS and DFS rates than in the isolated Ph group (p=0.091 and p=0.189, respectively). The Kaplan-Meier curves of patients with extra Ph or loss of 9/9p in the ACA group showed a tendency toward lower OS and DFS rates than in the isolated Ph group (p=0.018 and p=0.094, respectively) (Figure 5). However, the OS and DFS of patients with loss of 7/7p in the ACA group were not lower than in the isolated Ph group (p=0.152 and p=0.600, respectively) and also the OS and DFS of patients with complex karyotype in the ACA group were not lower than in the isolated Ph group (p=0.163 and p=0.729, respectively). We investigated OS and DFS according to ploidy levels in the patients of the ACA group who 7
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received HCT (Table 2). A comparison was performed between patients with each ploidy level and patients in the isolated Ph group. The patients with pseudodiploidy showed significant lower OS and DFS (p=0.025 and p=0.057, respectively). The patients with hyperdiploidy showed a tendency toward longer OS and DFS, compared to the patients with other ploidy levels. The total number of chromosomal abnormalities in patients with complex karyotypes ranged from 4 to 12, which included 0-9 numerical abnormalities and 1-7 structural abnormalities. However, we found no significant impact in the number of chromosomal aberrations on OS or DFS by survival analysis in patients with complex karyotypes. A multivariate Cox regression analysis of prognostic impact was performed for all patients (n=122) (Table 3). The hazard ratios (HRs) for OS and DFS in the ≥60 years old age group were low and not significant (p=0.428 and p=0.406, respectively). High white blood cell counts and low hemoglobin (Hb) levels were significantly associated with poor prognosis, but HCT was a negative predictor of poor prognosis. Extra Ph and loss of 9/9p were significantly associated with poor prognosis. The HRs of extra Ph and loss of 9/9p were 2.133 (p=0.017) and 2.161 (p=0.031), respectively, for OS, and 2.360 (p=0.024) and 3.429 (p=0.002), respectively, for DFS.
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Discussion ACAs in adult patients with Ph-positive ALL are very common. In this study, the frequency of ACAs among patients was 73.0%, which was slightly high compared to previous reports (42-71%) [1,914,19,20]. Before the use of TKI in chemotherapy for Ph-positive ALL in adults, ACAs showed no prognostic impact compared to patients with isolated Ph-positive ALL in several reports [1,10,13]. In other studies, however, specific types of ACAs showed a worse prognosis: 9p abnormalities and monosomy 7 were associated with a low CR rate, and supernumerary Ph, trisomy 8, and del(9p21) were associated with short relapse-free survival (RFS) [15,11]. The treatment modalities in those studies were heterogeneous because they used data from both patients who received HCT and patients who received chemotherapy only for the prognostic analysis of ACAs [10,12,13]. The introduction of TKI for the treatment of Ph-positive ALL significantly improved outcomes [21,22], and, as a result, new investigations of the prognostic impact of ACAs have been initiated. In the post-TKI era, patients with Ph-positive ALL, including ACAs, were found to have substantially poorer prognosis than patients with isolated Ph-positive ALL [9,14]. For now, however, the recurrent types of ACAs that contribute to poor prognosis, such as loss of 7/7p, remain debatable [9,14]. The recurrent types of ACAs found in this study were extra Ph, loss of 9/9p, loss of 7/7p, gain of 8/8q, gain of 9/9q, and gain of X, which were similar to the results from previous studies that identified frequencies of extra Ph, loss of 9/9p, loss of 7/7p as 17-33%, 12-30%, and 17-37%, respectively [1,9-15]. Other recurrent ACAs, including trisomy 21, high hyperdiploidy, gain of 14/14q, and duplication of 1q, were commonly reported in several prior studies [10-12,14], but were less frequent or rarely found in this study. Interestingly, when patients were divided into age groups in this study, the frequency of ACAs was not significantly different among the age groups, but the frequency was highest (81%) in young patients (19-30 years). In the young patient group, the frequency of extra Ph was higher than in other age groups (p=0.008). The population of young adult patients with ACAs has not been investigated previously; however, a study of childhood Ph-positive ALL patients reported that the frequency of extra Ph in the childhood patients with ACAs was 24%, which was similar to the frequency in adult patients in this study [23]. Several ALL Children’s Oncology Group (COG) protocols consider childhood ALL from ages 0-30, so the youngest group in this study can be considered as part of childhood rather than adult ALL [24,25]. The elimination of the 19-30-year age group from this study reduced the proportion of extra Ph from recurrent ACAs and reduced statistical significance of 9
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recurrent ACAs such as extra Ph and loss of 9/9p in survival analysis (data not shown). The high frequency of extra Ph in the 19-30-year age group is a new finding; further investigation is needed to better understand this finding. With the patients who received HCT, the ACA group definitely showed lower OS and DFS rates compared to the isolated Ph group. With the patients who received only chemotherapy including TKI, the ACA group showed a low tendency in OS and DFS compared to the isolated Ph group, although p value was >0.05. The sample size was too small to draw significant results for the patients who received only chemotherapy including TKI. The investigation of the prognostic significance of recurrent ACAs by the Kaplan-Meier method and log rank test revealed that the presence of extra Ph or loss of 9/9p mainly contributed to lower OS and DFS in the ACA group than in the isolated Ph group with the patients who received HCT. This was similar to the results from several previous reports: 9p anomalies were associated with a low CR rate and short median remission duration [11], extra Ph and del(9p21) showed significantly shorter RFS [15], extra Ph was associated with higher cumulative incidence of relapse (12), and loss of 9/9p was associated with inferior outcomes [14]. However, in this study, no prognostic difference was found between the patients with loss of 7/7p or complex karyotype in the ACA group and the patients in the isolated Ph group. Loss of 7/7p was frequently associated with inferior outcomes in previous reports [11,12,14]. The prognostic impact of loss of 7/7p, however, is debatable, because monosomy 7 showed no significant impact on RFS compared to extra Ph and del(9p21) [15], and patients without monosomy 7 in the ACA group showed inferior outcomes compared to the isolated Ph group of ALL patients who received HCT [9]. Complex karyotype in ACAs was associated with higher CR rate [12] or showed no significant difference in survival compared to patients without complex karyotype [14]. In this study, OS and DFS of the patients with hyperdiploidy in the ACA group were higher than in the patients with hypodiploidy or pseudodiploidy. This finding was similar to previous results of patients with hyperdiploidy who showed superior survival in ACA groups [11,26]. Multivariate Cox regression analysis of this study found that extra Ph and loss of 9/9p were associated with poor OS and DFS outcomes, with hazard ratios of 2-3. Extra Ph may contribute to the overexpression of BCR-ABL1 fusion transcript, and can cause TKI resistance. Loss of 9/9p can result in CDKN2 loss, which is a common type mutation reported in various cancers, including ALL. Also, multivariate analysis results showed that high WBC counts and a low Hb level were positive predictors, and HCT was a negative 10
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predictor for poor prognosis. Old age (≥60 years) did not show a significant result; this may be due to the high frequency of extra Ph in the young patients (19-30 years). Recently a study showing poor prognosis associated with extra Ph and loss of 9/9p in Ph positive ALL patients has been reported from a single institute [27]. Different from that report, our study shows a prognostic impact of extra Ph and loss of 9/9p in the patients who received HCT and more comprehensive analysis of cytogenetics and age-related distribution of recurrent ACAs. Although we retrospectively investigated the data of 122 patients from a 15-year time period at a single institute, the patient numbers may not have been sufficient to provide statistically significant results. Also, we used only the results from the conventional cytogenetics of G-banding technique for the analysis of ACAs. If we had used the results from more sensitive techniques, such as FISH, we may have found more significant results. In conclusion, Ph-positive ALL in adult patients can be genetically heterogeneous because ACAs are common and often accompany complex karyotypes. However, a few recurrent types of ACAs including extra Ph and loss of 9/9p seem to be significantly associated with poorer prognosis compared to the isolated Ph-positive ALL. The highest frequency of extra Ph in young patients can mask an age-related prognostic effect and the prognosis in young patients may not be better than in old patients. Therefore, the cytogenetic analysis at diagnosis and in monitoring of Ph-positive ALL is important for risk stratification and clinical decision making. Aggressive treatments need to be considered for the patients who have extra Ph or loss of 9/9p. We suggest that subclassification of ACAs could be applied to the prognostic investigation of Ph-positive ALL in adult patients.
Conflict of Interest The authors declare that they have no conflict of interest.
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Wrzesien-Kus A, Robak T, Pluta A, et al. Outcome of treatment in adults with Philadelphia chromosome-positive and/or BCR-ABL--positive acute lymphoblastic leukemia-retrospective analysis of Polish Adult Leukemia Group (PALG). Ann Hematol 2006;85:366-373.
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Li Y, Qiu L, Zou D, et al. Additional chromosomal abnormalities and their prognostic significance in adult Philadelphia-positive acute lymphoblastic leukemia: with or without imatinib in chemotherapy. Ann Hematol 2009;88:1069-1077.
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Primo D, Tabernero MD, Perez JJ, et al. Genetic heterogeneity of BCR/ABL+ adult B-cell precursor
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Crist W, Carroll A, Shuster J, et al. Philadelphia chromosome positive childhood acute lymphoblastic leukemia: clinical and cytogenetic characteristics and treatment outcome. A Pediatric Oncology Group study. Blood 1990;76:489-494.
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Gotz G, Weh HJ, Walter TA, et al. Clinical and prognostic significance of the Philadelphia chromosome in adult patients with acute lymphoblastic leukemia. Ann Hematol 1992;64:97100.
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Figure 1 The frequencies of ploidy levels and recurrent ACAs in ACA group. (A) The frequencies of ploidy levels: pseudodiploidy was found in 41.6%, hypodiploidy of 45 chromosomes in 21.3%, hypodiploidy of ≤44 chromosomes in 6.7%, hyperdiploidy of 47-50 chromosomes in 24.7%, hyperdiploidy of ≥51 chromosomes in 5.6% of ACA group. (B) The frequencies of recurrent ACAs: extra Ph was found in 24.7%, loss of 9/9p in 20.2%, loss of 7/7p in 19.1%, gain of 8/8q in 5.6%, gain of 9/9q in 5.6%, and gain of X in 4.5% of ACA group. Complex karyotype was found in 28.1% of ACA group. Figure 2 Number of ACAs across all chromosomes. (A) Number of numerical aberrations; the bars above the abscissa show the counts of chromosomal gains and the bars below the abscissa show the counts of chromosomal losses. (B) Number of structural aberrations; the bars above the abscissa show the counts of p-arm abnormalities and the bars below the abscissa show the counts of q-arm abnormalities. Figure 3 Frequencies of recurrent ACAs in age groups. The frequencies of recurrent ACAs including extra Ph, loss of 9/9p, loss of 7/7p, and complex karyotype were presented according to the age groups. * p-value of <0.05 in comparison to other age groups Figure 4 Comparison of OS and DFS between the ACA group and the isolated Ph group. The patients received HCT after chemotherapy including TKI. Figure 5 Comparison of OS and DFS between the patients with extra Ph or 9/9p loss in the ACA group and the isolated Ph group. The patients received HCT after chemotherapy including TKI.
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Table 1 Clinical and laboratory findings Isolated Ph
ACA
Number of patients
33 (27.0%)
89 (73.0%)
Age (years)
53 (19-74)
49 (20-80)
0.469
Male proportion (%)
45.5
51.7
0.541
WBC (x10 /L)
35.8 (2.0-569.3)
31.7 (1.2-481.4)
0.547
Hb (g/L)
91 (61-139)
99 (39-155)
0.159
Platelet (x10 /L)
54 (9-357)
56 (4-240)
0.220
Blasts in PB (%)
66 (0-98)
67 (0-97)
0.553
Serum LDH (U/L)
573 (145-3719)
645 (136-4626)
0.572
Common cell
81.8%
83.1%
0.904
Pro B
3.0%
3.4%
Pre B
15.2%
13.5%
Major
39.4%
28.1%
Minor
60.6%
71.9%
CTx with TKI and HCT (n=74)
57.6%
61.8%
0.682
CTx with TKI only (n=34)
30.3%
27.0%
0.715
CTx without TKI (n=7)
0.0%
7.9%
No CTx (n=7)
12.1%
3.4%
9
9
p-value
Immunophenotype
BCR-ABL1 fusion transcript 0.273
Treatment
Table 2 Comparison of survival according to ploidy levels in patients who received HCT OS (months)
DFS (months) p value
Mean
95% CI
Isolated Ph (n=19)
122.9
89.3 to 156.5
Ph/Pseudodiploidy (n=20)
51.8
31.2 to 72.4
Ph/Hypodiploidy (n=17)
66.1
Ph/Hyperdiploidy (n=18)
83.0
p value
Mean
95% CI
111.9
76.5 to 147.2
0.025
47.5
24.6 to 70.5
0.057
41.6 to 90.6
0.073
77.5
51.4 to 103.7
0.690
42.5 to 123.6
0.090
89.5
44.2 to 134.7
0.347
16
Page 16 of 18
Table 3 Results of multivariate Cox regression analysis OS
DFS
HR
95% CI
p value
HR
95% CI
p value
Age ≥ 60
0.751
0.369 to 1.525
0.428
0.676
0.269 to 1.702
0.406
WBC ≥ 50
1.938
1.144 to 3.283
0.014
1.758
0.935 to 3.308
0.080
Hb ≤ 10
1.743
1.038 to 2.926
0.036
1.913
1.011 to 3.619
0.046
LDH > 650
1.440
0.867 to 2.390
0.159
1.920
1.035 to 3.560
0.038
HCT
0.230
0.115 to 0.458
0.000
0.236
0.100 to 0.557
0.001
Extra Ph
2.133
1.143 to 3.979
0.017
2.360
1.119 to 4.979
0.024
9/9p loss
2.161
1.072 to 4.358
0.031
3.429
1.574 to 7.468
0.002
7/7p loss
1.184
0.609 to 2.302
0.619
0.918
0.408 to 2.064
0.835
Complex
0.931
0.496 to 1.746
0.824
0.838
0.405 to 1.735
0.634
17
Page 17 of 18
18
Page 18 of 18
S2210-7762(17)30080-7 http://dx.doi.org/doi: 10.1016/j.cancergen.2017.06.001 CGEN 531
To appear in:
Cancer Genetics
Received date: Revised date: Accepted date:
7-3-2017 19-5-2017 7-6-2017
Please cite this article as: Chang Ahn Seol, Young-Uk Cho, Seongsoo Jang, Chan-Jeoung Park, Jung-Hee Lee, Je-Hwan Lee, Kyoo Hyung Lee, Eul-Ju Seo, Prognostic Significance of Recurrent Additional Chromosomal Abnormalities in Adult Patients with Philadelphia ChromosomePositive Acute Lymphoblastic Leukemia, Cancer Genetics (2017), http://dx.doi.org/doi: 10.1016/j.cancergen.2017.06.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Original Article
Prognostic Significance of Recurrent Additional Chromosomal Abnormalities in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
a
a
a
a
b
Chang Ahn Seol , Young-Uk Cho , Seongsoo Jang , Chan-Jeoung Park , Jung-Hee Lee , Jeb
b
a,
Hwan Lee , Kyoo Hyung Lee , Eul-Ju Seo * a
Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical
Center, Seoul, Korea;
b
Department of Internal Medicine, University of Ulsan College of Medicine and
Asan Medical Center, Seoul, Korea
* Corresponding author: Eul-Ju Seo, M.D. Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: +82 2 3010 4507, Fax: +82 2 478 0884, E-mail: [email protected]
1
Page 1 of 18
Abstract In Philadelphia (Ph)
chromosome-positive acute
lymphoblastic
leukemia (ALL), additional
chromosomal abnormalities (ACAs) are frequently observed. We investigated the cytogenetic characteristics and prognostic significance of ACAs in Ph-positive ALL. We reviewed the clinical data and bone marrow cytogenetic findings of 122 adult Ph-positive ALL patients. The ACAs were examined for partial or whole chromosomal gains or losses, and structural aberrations. The overall survival (OS) and disease-free survival (DFS) of patients who received hematopoietic cell transplantation were compared between the isolated Ph group and ACA group. ACAs were present in 73.0% of all patients. The recurrent ACAs were extra Ph (24.7%), 9/9p loss (20.2%), and 7/7p loss (19.1%). Complex karyotype was found in 28.1% of patients in the ACA group. Younger patients (1930 years) in the ACA group showed the highest frequency of extra Ph (54%) compared to other age groups. The OS in the ACA group was significantly shorter than in the isolated Ph group. The presence of an extra Ph chromosome or 9/9p loss was significantly associated with shorter OS and DFS, whereas 7/7p loss and complex karyotype were not associated with poorer prognosis. We suggest that subclassification of ACAs could be applied to prognostic investigation of Ph-positive ALL. Keywords Acute lymphoblastic leukemia, Philadelphia chromosome-positive, additional chromosomal abnormality, prognosis
2
Page 2 of 18
Introduction The Philadelphia (Ph) chromosome is the most common chromosomal aberration in adult acute lymphoblastic leukemia (ALL) and is associated with an unfavorable prognosis. The Ph chromosome is observed in 15-30% of adult ALL patients, compared to 2-4% of children with ALL; the frequency of the Ph chromosome can approach 50% in 40-50-year-old ALL patients [1-6]. Additional chromosomal abnormalities (ACAs) are frequently observed in Ph-positive ALL patients, compared to chronic myelogenous leukemia patients in the chronic phase [7,8]. In previous studies, the frequency of ACAs in Ph-positive adult ALL patients was 42-71% [1,9-13]. However, the prognostic impact of ACAs has not been established and controversies regarding the impact of ACAs remain. In several reports, ACAs in Ph-positive ALL patients were not associated with a worse prognosis compared to those in isolated Ph-positive ALL patients [1,10,13]. In other studies, Ph-positive ALL patients with ACAs showed a worse prognosis compared to the isolated Ph-positive ALL patients [9,11,12,14,15]. Whether recurrent ACAs such as 7/7p loss are associated with poor prognosis is debatable [9,12]. Studies on ACAs in Ph-positive ALL patients, especially in the post tyrosine kinase inhibitor (TKI) era, are lacking [9,14]. In this study, we retrospectively investigated the frequency and prognostic impact of ACAs in Ph-positive adult ALL patients from a single institute. The investigation was focused on the analysis of recurrent abnormalities in the ACAs and the prognostic significance of the recurrent ACAs in the patients who received hematopoietic cell transplantation (HCT).
3
Page 3 of 18
Materials and Methods Patients The subjects of this study comprised 122 patients diagnosed with Ph chromosome-positive ALL between 2000 and 2015 at the Asan Medical Center, Seoul, Korea. The diagnosis of Ph-positive ALL was performed according to the WHO classification of tumors of hematopoietic and lymphoid tissues [16]. Subjects were required to be 19 years of age or older at the time of diagnosis for inclusion in the study. The median age of the subjects was 49.5 years (19-80). We retrospectively reviewed the clinical data, laboratory findings, and cytogenetic findings of the bone marrow (BM) aspirate from the medical records of each subject. The clinical and laboratory findings included age, sex, complete blood cell counts and blast percentage in peripheral blood (PB), serum lactate dehydrogenase (LDH) level, results of immunophenotypic analysis, major or minor BCR-ABL1 fusion transcript, and treatment modalities such as chemotherapy and HCT. The subjects were assigned to the isolated-Ph group or the ACA group. The clinical and laboratory findings were compared between the 2 groups. This study was approved by the Institutional Review Board of the Asan Medical Center, Seoul, Korea. Treatment The induction chemotherapy comprised vincristine, daunorubicin, TKI (imatinib or dasatinib), and steroid
treatment
(prednisolone,
methyl
prednisolone,
or
dexamethasone).
Consolidation
chemotherapy comprised cyclophosphamide, cytosine arabinoside, high-dose methotrexate, TKI, and steroid treatment. Central nervous system prophylaxis was performed by intrathecal methotrexate injection. For the patients who received HCT after chemotherapy including TKI (n=74), the conditioning
regimen
comprised
busulfan,
fludarabine,
methotrexate,
and
antithymocyte
immunoglobulin. The study subjects included the patients who received only chemotherapy including TKI (n=34), the patients who received only chemotherapy without TKI (n=7), and the patients who did not receive chemotherapy (n=7). Complete remission (CR) was defined according to the ALL response criteria of the National Comprehensive Cancer Network [17]. Relapse was defined as reappearance of lymphoblasts accounting for more than 5% of the nucleated cells in BM, or appearance of extramedullary leukemia, after CR. Cytogenetic analysis BM cells were cultured with RPMI-1640 working medium and fetal bovine serum for 24 and 48 hours in a 37°C 5% CO2 incubator. Using colcemid and 0.075 M potassium chloride solution, the metaphase 4
Page 4 of 18
cells were harvested. The metaphase cells were stained by GTL-banding technique. At least 20 metaphase cells were analyzed in each patient. The results of chromosomal analysis were described according to the International System for Human Cytogenetic Nomenclature [18]. The ACAs from the karyotype descriptions were examined for partial or whole chromosomal gains or losses, and structural aberrations. A complex karyotype was defined as having equal to or more than 4 independent chromosomal aberrations. The type and frequency of recurrent ACAs were investigated in the patients in the ACA group. The patients were divided into 5 age groups (19-30 years, 31-40 years, 41-50 years, 51-60 years and >60 years group) and the frequencies of ACAs were also investigated in each age group. Statistical analysis The quantitative data were presented as medians (ranges). The comparison of the clinical and laboratory data between the ACA group and the isolated-Ph group was performed by Mann Whitney U-test or Pearson’s Chi-square test. The comparisons of the frequencies of recurrent ACAs in the age groups were performed by Pearson’s Chi-square test or Fisher’s exact test. Overall survival (OS) was defined as time from date of diagnosis to time of death for any reason. The disease-free survival (DFS) was defined as time from date of CR to date of relapse or death for any reason. The 5-year survival rate was presented as an estimated rate ± standard error and the median survival was presented as an estimated survival ± standard error. The OS and DFS in the patients who received HCT were analyzed by the Kaplan-Meier method, and the outcomes were compared between the ACA group and the isolated Ph group by the log-rank test. The OS and DFS in the patients who received only chemotherapy including TKI were also compared between the ACA group and the isolated Ph group. Cox proportional hazard models for multivariate analysis were used to investigate hazard ratios of recurrent ACAs for the total patients. SPSS 19.0 (IBM, Chicago, USA) was used for the statistical analysis and a p-value of <0.05 was considered statistically significant.
5
Page 5 of 18
Results Clinical and laboratory data The clinical and laboratory findings are summarized in Table 1. ACAs were present in 73.0% of total patients with Ph-chromosome positive ALL. The incidence of patients with ACAs was not significantly different by sex or age. The median age and male proportion were 53 years and 45.5% in the isolated Ph group, compared to 49 years and 51.7% in the ACA group. The complete blood cell counts were not significantly different between the isolated Ph group and the ACA group. The blast counts in PB, serum LDH level, the immunophenotype of BM flow cytometry, and the proportion of major and minor BCR-ABL1 transcripts in the ACA group were compared with the results in the isolated Ph group; no statistically significant difference was found. The proportion of patients who received HCT after chemotherapy including TKI in the isolated Ph group and in the ACA group was 57.6% and 61.8%, respectively (p=0.682). Cytogenetic analysis of ACAs Based on the cytogenetic results of the ACA group, the frequencies of the ploidy levels of the karyotypes and recurrent ACAs are presented in Figure 1. According to the ploidy levels of the karyotypes, pseudodiploidy was the most common, and found in 41.6% of the patients in the ACA group. Hypodiploidy of 45 chromosomes was found in 21.3% of patients, and hyperdiploidy of 47 to 50 chromosomes was found in 24.7% of the patients in the ACA group. The ACAs included recurrent types of ACAs, such as extra Ph (24.7%), loss of 9/9p (20.2%), and loss of 7/7p (19.1%). Complex karyotype was present in 28.1% of the patients in the ACA group. The distributions of numerical and structural aberrations are presented across all chromosomes in Figure 2. Monosomy 7 and monosomy 9 were frequently observed as numerical aberrations (Figure 2A). Moreover, 7p, 9p and 22q abnormalities were frequently observed as structural aberrations (Figure 2B). Frequent 22q abnormalities were due to extra Ph. The frequency of ACAs by age group did not differ significantly; the frequency was 81% (n=16), 72% (n=18), 77% (n=30), 62% (n=29), and 76% (n=29) in the 19-30-year, 31-40-year, 41-50year, 51-60-year, and >60-year age groups, respectively. The frequencies of recurrent ACAs, such as extra Ph, loss of 9/9p, loss of 7/7p, and complex karyotype in the patients with ACAs, by age group, are presented in Figure 3. In the 19-30-year-age group, the frequency of extra Ph (54%) was significantly higher than in other age groups (p=0.008). Complex karyotypes were frequently observed 6
Page 6 of 18
across all the age categories in the ACA group. They comprised structural aberrations such as unbalanced translocations (88%) and balanced translocations (16%) and numerical aberrations such as trisomies (36%) and monosomies (44%) and the distributions of those aberrations in complex karyotypes were not different across the age categories. Prognostic analysis of ACAs For the patients who received HCT (n=74), the comparison of OS and DFS was performed between the ACA group (n=55) and the isolated Ph group (n=19). The median follow-up time after diagnosis in the ACA group was 31 months (4.8-166 months), compared to 53 months (12-169 months) in the isolated Ph group. The 5-year OS rate of 40.5±7.7% in the ACA group was significantly lower than the 5-year OS rate of 76.5±10.3% in the isolated Ph group (p=0.024). The 5-year DFS rate of 45.9±8.5% in the ACA group showed a low tendency compared to the 5-year DFS rate of 61.1±12.6% in the isolated Ph group (p=0.195) (Figure 4). For the patients who only received chemotherapy including TKI (n=34), the comparison of OS and DFS was also performed between the ACA group (n=24) and the isolated Ph group (n=10). The median OS was 11.5±3.1 months in the ACA group compared to 25.3±15.8 months in the isolated Ph group (p=0.663) and the median DFS was 17.6±10.0 months in the ACA group compared to 22.8±1.5 months in the isolated Ph group (p=0.985). For the patients who received HCT (n=74), we analyzed the prognostic impact of recurrent ACAs, such as extra Ph, loss of 9/9p, loss of 7/7p, and complex karyotype. The 5-year OS and DFS rates of patients with extra Ph in the ACA group were 31.6±13.2% and 34.1±14.9%, respectively, and the Kaplan-Meier curves showed a tendency toward lower OS and DFS rates than in the isolated Ph group (p=0.014 and p=0.072, respectively). The 5-year OS and DFS rates of patients with loss of 9/9p in the ACA group were 44.0%±14.3 and 34.3±15.3%, respectively, and the Kaplan-Meier curves showed a tendency toward lower OS and DFS rates than in the isolated Ph group (p=0.091 and p=0.189, respectively). The Kaplan-Meier curves of patients with extra Ph or loss of 9/9p in the ACA group showed a tendency toward lower OS and DFS rates than in the isolated Ph group (p=0.018 and p=0.094, respectively) (Figure 5). However, the OS and DFS of patients with loss of 7/7p in the ACA group were not lower than in the isolated Ph group (p=0.152 and p=0.600, respectively) and also the OS and DFS of patients with complex karyotype in the ACA group were not lower than in the isolated Ph group (p=0.163 and p=0.729, respectively). We investigated OS and DFS according to ploidy levels in the patients of the ACA group who 7
Page 7 of 18
received HCT (Table 2). A comparison was performed between patients with each ploidy level and patients in the isolated Ph group. The patients with pseudodiploidy showed significant lower OS and DFS (p=0.025 and p=0.057, respectively). The patients with hyperdiploidy showed a tendency toward longer OS and DFS, compared to the patients with other ploidy levels. The total number of chromosomal abnormalities in patients with complex karyotypes ranged from 4 to 12, which included 0-9 numerical abnormalities and 1-7 structural abnormalities. However, we found no significant impact in the number of chromosomal aberrations on OS or DFS by survival analysis in patients with complex karyotypes. A multivariate Cox regression analysis of prognostic impact was performed for all patients (n=122) (Table 3). The hazard ratios (HRs) for OS and DFS in the ≥60 years old age group were low and not significant (p=0.428 and p=0.406, respectively). High white blood cell counts and low hemoglobin (Hb) levels were significantly associated with poor prognosis, but HCT was a negative predictor of poor prognosis. Extra Ph and loss of 9/9p were significantly associated with poor prognosis. The HRs of extra Ph and loss of 9/9p were 2.133 (p=0.017) and 2.161 (p=0.031), respectively, for OS, and 2.360 (p=0.024) and 3.429 (p=0.002), respectively, for DFS.
8
Page 8 of 18
Discussion ACAs in adult patients with Ph-positive ALL are very common. In this study, the frequency of ACAs among patients was 73.0%, which was slightly high compared to previous reports (42-71%) [1,914,19,20]. Before the use of TKI in chemotherapy for Ph-positive ALL in adults, ACAs showed no prognostic impact compared to patients with isolated Ph-positive ALL in several reports [1,10,13]. In other studies, however, specific types of ACAs showed a worse prognosis: 9p abnormalities and monosomy 7 were associated with a low CR rate, and supernumerary Ph, trisomy 8, and del(9p21) were associated with short relapse-free survival (RFS) [15,11]. The treatment modalities in those studies were heterogeneous because they used data from both patients who received HCT and patients who received chemotherapy only for the prognostic analysis of ACAs [10,12,13]. The introduction of TKI for the treatment of Ph-positive ALL significantly improved outcomes [21,22], and, as a result, new investigations of the prognostic impact of ACAs have been initiated. In the post-TKI era, patients with Ph-positive ALL, including ACAs, were found to have substantially poorer prognosis than patients with isolated Ph-positive ALL [9,14]. For now, however, the recurrent types of ACAs that contribute to poor prognosis, such as loss of 7/7p, remain debatable [9,14]. The recurrent types of ACAs found in this study were extra Ph, loss of 9/9p, loss of 7/7p, gain of 8/8q, gain of 9/9q, and gain of X, which were similar to the results from previous studies that identified frequencies of extra Ph, loss of 9/9p, loss of 7/7p as 17-33%, 12-30%, and 17-37%, respectively [1,9-15]. Other recurrent ACAs, including trisomy 21, high hyperdiploidy, gain of 14/14q, and duplication of 1q, were commonly reported in several prior studies [10-12,14], but were less frequent or rarely found in this study. Interestingly, when patients were divided into age groups in this study, the frequency of ACAs was not significantly different among the age groups, but the frequency was highest (81%) in young patients (19-30 years). In the young patient group, the frequency of extra Ph was higher than in other age groups (p=0.008). The population of young adult patients with ACAs has not been investigated previously; however, a study of childhood Ph-positive ALL patients reported that the frequency of extra Ph in the childhood patients with ACAs was 24%, which was similar to the frequency in adult patients in this study [23]. Several ALL Children’s Oncology Group (COG) protocols consider childhood ALL from ages 0-30, so the youngest group in this study can be considered as part of childhood rather than adult ALL [24,25]. The elimination of the 19-30-year age group from this study reduced the proportion of extra Ph from recurrent ACAs and reduced statistical significance of 9
Page 9 of 18
recurrent ACAs such as extra Ph and loss of 9/9p in survival analysis (data not shown). The high frequency of extra Ph in the 19-30-year age group is a new finding; further investigation is needed to better understand this finding. With the patients who received HCT, the ACA group definitely showed lower OS and DFS rates compared to the isolated Ph group. With the patients who received only chemotherapy including TKI, the ACA group showed a low tendency in OS and DFS compared to the isolated Ph group, although p value was >0.05. The sample size was too small to draw significant results for the patients who received only chemotherapy including TKI. The investigation of the prognostic significance of recurrent ACAs by the Kaplan-Meier method and log rank test revealed that the presence of extra Ph or loss of 9/9p mainly contributed to lower OS and DFS in the ACA group than in the isolated Ph group with the patients who received HCT. This was similar to the results from several previous reports: 9p anomalies were associated with a low CR rate and short median remission duration [11], extra Ph and del(9p21) showed significantly shorter RFS [15], extra Ph was associated with higher cumulative incidence of relapse (12), and loss of 9/9p was associated with inferior outcomes [14]. However, in this study, no prognostic difference was found between the patients with loss of 7/7p or complex karyotype in the ACA group and the patients in the isolated Ph group. Loss of 7/7p was frequently associated with inferior outcomes in previous reports [11,12,14]. The prognostic impact of loss of 7/7p, however, is debatable, because monosomy 7 showed no significant impact on RFS compared to extra Ph and del(9p21) [15], and patients without monosomy 7 in the ACA group showed inferior outcomes compared to the isolated Ph group of ALL patients who received HCT [9]. Complex karyotype in ACAs was associated with higher CR rate [12] or showed no significant difference in survival compared to patients without complex karyotype [14]. In this study, OS and DFS of the patients with hyperdiploidy in the ACA group were higher than in the patients with hypodiploidy or pseudodiploidy. This finding was similar to previous results of patients with hyperdiploidy who showed superior survival in ACA groups [11,26]. Multivariate Cox regression analysis of this study found that extra Ph and loss of 9/9p were associated with poor OS and DFS outcomes, with hazard ratios of 2-3. Extra Ph may contribute to the overexpression of BCR-ABL1 fusion transcript, and can cause TKI resistance. Loss of 9/9p can result in CDKN2 loss, which is a common type mutation reported in various cancers, including ALL. Also, multivariate analysis results showed that high WBC counts and a low Hb level were positive predictors, and HCT was a negative 10
Page 10 of 18
predictor for poor prognosis. Old age (≥60 years) did not show a significant result; this may be due to the high frequency of extra Ph in the young patients (19-30 years). Recently a study showing poor prognosis associated with extra Ph and loss of 9/9p in Ph positive ALL patients has been reported from a single institute [27]. Different from that report, our study shows a prognostic impact of extra Ph and loss of 9/9p in the patients who received HCT and more comprehensive analysis of cytogenetics and age-related distribution of recurrent ACAs. Although we retrospectively investigated the data of 122 patients from a 15-year time period at a single institute, the patient numbers may not have been sufficient to provide statistically significant results. Also, we used only the results from the conventional cytogenetics of G-banding technique for the analysis of ACAs. If we had used the results from more sensitive techniques, such as FISH, we may have found more significant results. In conclusion, Ph-positive ALL in adult patients can be genetically heterogeneous because ACAs are common and often accompany complex karyotypes. However, a few recurrent types of ACAs including extra Ph and loss of 9/9p seem to be significantly associated with poorer prognosis compared to the isolated Ph-positive ALL. The highest frequency of extra Ph in young patients can mask an age-related prognostic effect and the prognosis in young patients may not be better than in old patients. Therefore, the cytogenetic analysis at diagnosis and in monitoring of Ph-positive ALL is important for risk stratification and clinical decision making. Aggressive treatments need to be considered for the patients who have extra Ph or loss of 9/9p. We suggest that subclassification of ACAs could be applied to the prognostic investigation of Ph-positive ALL in adult patients.
Conflict of Interest The authors declare that they have no conflict of interest.
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Page 11 of 18
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Termuhlen AM, Smith LM, Perkins SL, et al. Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children's Oncology Group trial A5971: a report from the Children's Oncology Group. Pediatr Blood Cancer 2012;59:1229-1233.
26.
Tauro S, McMullan D, Griffiths M, et al. High-hyperdiploidy in Philadelphia positive adult acute lymphoblastic leukaemia: case-series and review of literature. Bone Marrow Transplant 2003;31:763-766.
27.
Short NJ, Kantarjian HM, Sasaki K, et al. Poor outcomes associated with +der(22)t(9;22) and -9/9p in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia receiving chemotherapy plus a tyrosine kinase inhibitor. Am J Hematol 2017;92:238-243.
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Figure 1 The frequencies of ploidy levels and recurrent ACAs in ACA group. (A) The frequencies of ploidy levels: pseudodiploidy was found in 41.6%, hypodiploidy of 45 chromosomes in 21.3%, hypodiploidy of ≤44 chromosomes in 6.7%, hyperdiploidy of 47-50 chromosomes in 24.7%, hyperdiploidy of ≥51 chromosomes in 5.6% of ACA group. (B) The frequencies of recurrent ACAs: extra Ph was found in 24.7%, loss of 9/9p in 20.2%, loss of 7/7p in 19.1%, gain of 8/8q in 5.6%, gain of 9/9q in 5.6%, and gain of X in 4.5% of ACA group. Complex karyotype was found in 28.1% of ACA group. Figure 2 Number of ACAs across all chromosomes. (A) Number of numerical aberrations; the bars above the abscissa show the counts of chromosomal gains and the bars below the abscissa show the counts of chromosomal losses. (B) Number of structural aberrations; the bars above the abscissa show the counts of p-arm abnormalities and the bars below the abscissa show the counts of q-arm abnormalities. Figure 3 Frequencies of recurrent ACAs in age groups. The frequencies of recurrent ACAs including extra Ph, loss of 9/9p, loss of 7/7p, and complex karyotype were presented according to the age groups. * p-value of <0.05 in comparison to other age groups Figure 4 Comparison of OS and DFS between the ACA group and the isolated Ph group. The patients received HCT after chemotherapy including TKI. Figure 5 Comparison of OS and DFS between the patients with extra Ph or 9/9p loss in the ACA group and the isolated Ph group. The patients received HCT after chemotherapy including TKI.
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Table 1 Clinical and laboratory findings Isolated Ph
ACA
Number of patients
33 (27.0%)
89 (73.0%)
Age (years)
53 (19-74)
49 (20-80)
0.469
Male proportion (%)
45.5
51.7
0.541
WBC (x10 /L)
35.8 (2.0-569.3)
31.7 (1.2-481.4)
0.547
Hb (g/L)
91 (61-139)
99 (39-155)
0.159
Platelet (x10 /L)
54 (9-357)
56 (4-240)
0.220
Blasts in PB (%)
66 (0-98)
67 (0-97)
0.553
Serum LDH (U/L)
573 (145-3719)
645 (136-4626)
0.572
Common cell
81.8%
83.1%
0.904
Pro B
3.0%
3.4%
Pre B
15.2%
13.5%
Major
39.4%
28.1%
Minor
60.6%
71.9%
CTx with TKI and HCT (n=74)
57.6%
61.8%
0.682
CTx with TKI only (n=34)
30.3%
27.0%
0.715
CTx without TKI (n=7)
0.0%
7.9%
No CTx (n=7)
12.1%
3.4%
9
9
p-value
Immunophenotype
BCR-ABL1 fusion transcript 0.273
Treatment
Table 2 Comparison of survival according to ploidy levels in patients who received HCT OS (months)
DFS (months) p value
Mean
95% CI
Isolated Ph (n=19)
122.9
89.3 to 156.5
Ph/Pseudodiploidy (n=20)
51.8
31.2 to 72.4
Ph/Hypodiploidy (n=17)
66.1
Ph/Hyperdiploidy (n=18)
83.0
p value
Mean
95% CI
111.9
76.5 to 147.2
0.025
47.5
24.6 to 70.5
0.057
41.6 to 90.6
0.073
77.5
51.4 to 103.7
0.690
42.5 to 123.6
0.090
89.5
44.2 to 134.7
0.347
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Table 3 Results of multivariate Cox regression analysis OS
DFS
HR
95% CI
p value
HR
95% CI
p value
Age ≥ 60
0.751
0.369 to 1.525
0.428
0.676
0.269 to 1.702
0.406
WBC ≥ 50
1.938
1.144 to 3.283
0.014
1.758
0.935 to 3.308
0.080
Hb ≤ 10
1.743
1.038 to 2.926
0.036
1.913
1.011 to 3.619
0.046
LDH > 650
1.440
0.867 to 2.390
0.159
1.920
1.035 to 3.560
0.038
HCT
0.230
0.115 to 0.458
0.000
0.236
0.100 to 0.557
0.001
Extra Ph
2.133
1.143 to 3.979
0.017
2.360
1.119 to 4.979
0.024
9/9p loss
2.161
1.072 to 4.358
0.031
3.429
1.574 to 7.468
0.002
7/7p loss
1.184
0.609 to 2.302
0.619
0.918
0.408 to 2.064
0.835
Complex
0.931
0.496 to 1.746
0.824
0.838
0.405 to 1.735
0.634
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