Fluorescence in situ hybridization comparison of the prognostic factors in adult and pediatric acute lymphoblastic leukemia: A retrospective analysis of 282 cases
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- Published online on: October 2, 2018 https://doi.org/10.3892/etm.2018.6821
- Pages: 4674-4684
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Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Acute lymphoblastic leukemia (ALL) affects both children and adults, with peak prevalence between the ages of 2–5 years and again after the age of 50 years (1). Overall age-adjusted incidence is 1.7 per 100,000 persons; roughly 60% of cases are diagnosed in patients younger than 20 years (2). ALL development includes genetic instability such as translocation and fusion genes. The relevance of the prognosis and cytogenetic abnormalities between adult ALL and pediatric ALL has been studied for decades (3–5). Retrospective studies (6,7) by diverse departments and various institutions worldwide have revealed that 20% of adult patients with ALL have the BCR-ABL fusion protein, while only ~5% of pediatric patients with ALL harbor the Philadelphia (Ph) chromosome at present. Due to the high frequency of unfavorable cytogenetic features such as t(9;22)(q34;q11) and t(1;19)(q23;p13), the outcome of treatment in ALL worsens with age (8).
During the last decade, the advances in our understanding of the clinical, immunobiological and genetic characteristics of ALL have led to improved risk stratification and to risk-adapted treatment strategies. In addition to conventional chemotherapy, stem cell (or bone marrow) transplant and chimeric antigen receptor T-cell therapy are used for certain unusual subtypes of ALL or refractory B-cell ALL. Monoclonal antibodies, new immunotherapy treatments and other targeted approaches are promising novel therapeutic approaches to ALL. With the current therapies, the vast majority of pediatric patients with ALL are now long-term survivors. In China, the 5-year and 10-year overall survival rates are 80.0±1.2 and 76.3±1.6%, respectively (9). In developed countries, the 5-year overall survival rate for ALL has increased to 90% in the last 30 years (10). Unfortunately, the same positive results have not been obtained for adult patients with ALL (11). In adult ALL, the cure rate is estimated to be 20–40% (12). Adults present with higher risk features at diagnosis, which predispose them to chemotherapy resistance and disease relapse after an initial achievement of complete remission (CR). The incorporation of targeted agents into adult ALL therapy has improved survival in several subsets (13,14). In the present study, the cryptic chromosomal alterations and genomic changes in a cohort of 75 adult ALL samples and 207 pediatric ALL samples were investigated. The cytogenetic abnormalities and prognosis of the two groups were analyzed using fluorescence in situ hybridization (FISH) in order to determine why survival is poorer in adult ALL than in pediatric ALL. The results indicate that adult ALL has a poorer prognosis compared with pediatric ALL based on Ph+ status and presence of trisomy 4 or 10. Ph+ is an independent prognosis factor of ALL.
Patients and methods
Patient characteristics
All ALL cases enrolled in the present study were diagnosed and treated at the Department of Hematology, Xiangya Hospital (Changsha, China) from January 2008-December 2012. Consecutive patients were enrolled, giving a total of 207 pediatric patients and 75 adult patients. Written informed consent was obtained from all patients. In order to maintain consistent treatment, patients who received HSCT or had never received chemotherapy were excluded from the study. All patients underwent blood routine examination, bone marrow (BM) aspiration, Wright's and peroxidase (POX) staining, cerebrospinal fluid, immunophenotyping and FISH examination. In addition, the pretreatment workup included a complete medical history, physical examination, chest X-ray, B-ultrasound scan of the abdomen and neck and routine laboratory analysis. Table I presents the characteristics of the whole cohort. The Xiangya Hospital Ethics Committee approved the present study (approval no. 201212478).
Immunophenotyping and FISH
Immunophenotype analysis was performed on BM specimens of 269 of 282 cases using a BD FACSCanto II flow cytometry instrument (BD Biosciences, Franklin Lakes, NJ, USA). The other 13 patients had no available immunophenotype analysis and were excluded from this assay. BM samples were stored at 4°C prior to the assay and all samples were assessed within 24 h of collection. All antibody reagents were purchased from BD Biosciences. The ALL marker panel used was as follows: (CD) 45-PerCP (cat no. 347464), CD34-APC (cat no. 743533), CD19-PE Cy7 (cat no. 745907), CD10-FITC (cat no. 745553), CD20-APC (cat no. 743611), cytoplasmic CD22-PE (cat no. 562859), CD2-FITC (cat no. 745734), CD3-APC (cat no. 746776), cytoplasmic CD3-APC (cat no. 340440), CD5-APC (cat no. 742554), CD7-FITC (cat no. 562635), CD13-PE (cat no. 555394), CD33-APC (cat no. 551378), surface immunoglobulin M (IgM)-APC (cat no. 560575) and cytoplasmic IgM-APC (cat no. 560914). All the antibodies were diluted 1:100 and were detected by direct immunofluorescence using a flow cytometer. Data were analyzed by FACSDiva 6.0 (BD Biosciences).
The multiprobe ALL panel was designed to detect eight FISH probes: BCR/ABL translocation, mixed lineage leukemia (MLL) rearrangement, translocation ETS leukemia-acute myeloid leukemia 1 (TEL-AML1) fusion gene and trisomy 4/10. The probes are located at 22q11.2 9q34, 11q23, 12p13 21q22, and 4p11.1-q11.1/10p11.1-q11.1, which represent the chromosome abnormalities t(9;22)(q34;qll), 11q23, t(12;21)(p13;q22) and trisomy 4/10, respectively. A total of 2 ml fresh BM was taken from each patient prior to treatment. The BM was centrifuged at 12,00 rpm for 10 min at room temperature to extract nucleated cells. Cells were subjected to hypotonic shock, fixed with methanol and acetic acid, then a cell suspension was prepared for FISH detection. FISH probes were purchased from Beijing GP Medical Technologies, Ltd., Beijing, China) and marked by nick translation. FISH was performed according to the manufacturer's instructions FISH probes are reversibly bound to the surface of a glass device, and dissolve upon contact with hybridization buffer, which is composed of formamide, SSC and glucan sulfate; probe and target DNA denaturation occurs simultaneously upon heating at 78°C for 5 min. Hybridization conditions were 42°C for 14–16 h. Probe cut-off values were established by testing 20 BM samples from healthy individuals (median age, 31 years; range, 18–50 years old; male to female ratio, 1.5:1; enrolled at Xiangya Hospital from May to December 2011, with informed consent). Data from 500 interphase cells were gathered from each individual in the control group to establish a normal database for the probes. The cut-off values for the Ph chromosome, trisomy 4, trisomy 10, MLL gene, and TEL-AML1 gene were 4.08, 2.32, 2.88, 3.24 and 3.76%, respectively.
Diagnosis and subclassification
ALL diagnosis was mainly based on morphology of BM and immunotyping of flow cytometry (15,16): The proportion of primitive and juvenile lymphocytes in BM was >20%, which was the basic diagnosis requirement. Morphology diagnosis performed using routine procedures: Methanol fixing, Wright staining and POX staining, then cell morphology was examined with an optical microscope (Olympus CX21; Olympus, Japan, Tokyo). Flow cytometry served a crucial role in differential diagnosis and subclassification: Strong CD19 expression associated with weak expression of CD10, CD22, or CD79a or weak CD19 expression plus strong expression of two of the same markers were considered as B lineage; strong cytoplasmic or surface CD3 expression was considered as T lineage; CD5 or CD7 indicated pre-T-ALL and early pre-T-ALL; and ambiguous B-lineage or T-lineage markers, or ‘bilineal’ cases were considered as uncertain-lineage subtypes. All patients received the standard treatment strategies according to the National Comprehensive Cancer Network guideline (17). Remission-induction therapy, consolidation phase and maintenance chemotherapy comprise an integrity program for patients who achieved continued CR until the analysis of the present study. Adult patients received CVMD (cyclophosphamide, vincristine, mitoxantrone and dexamethasone), R-CVMDL (rituximab in combination with cyclophosphamide, vincristine, mitoxantrone, dexamethasone and L-asparaginase), or R-CHOP (rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone) treatment regimens, whereas pediatric patients were treated with VDLD (vincristine, daunorubicin, L-asparaginase and dexamethasone) or VDLP (vincristine, daunorubicin, L-asparaginase and prednisone) therapeutic regimens.
Follow-up
Follow-up was measured from the initial day of treatment to the final follow-up date (January 2015), or the day the patient succumbed. Following treatment, follow-up examinations were conducted every 3–6 months in the first 2 years, every month in the following 3 years and annually thereafter. The duration of overall survival (OS) was calculated from the day of treatment completion to the day of mortality or the final follow-up; the event-free survival (EFS) rate was calculated from the day of treatment completion to the day of tumor progression, the occurrence of fatal or intolerable side effects or mortality.
Statistical analysis
Statistical analyses were performed using SPSS 17.0 (SPSS, Inc., Chicago, IL, USA). The χ2 test was used for comparing clinical and biological features between the 282 adults and pediatric ALL cases. Prognostic factors, including leukocyte count, hemoglobin level, BCR-ABL translocation, MLL rearrangement, and immunophenotype were analyzed. Multivariate analysis was performed to identify the independent prognostic factors. The OS and EFS rates were calculated using the Kaplan-Meier method and were compared using the log-rank test. P<0.05 was considered to indicate a statistically significant difference.
Results
Clinical characteristics of patients
The median follow-up time was 46 months (range, 3–68 months), with 96.8% of patients finishing a complete 3-year follow-up. The median age of the 207 pediatric ALL cases was 5.4 years (range, 0.5–14 years); that of the 75 adult ALL cases was 32.9 years (range, 15–68 years). Table I presents the other patient clinical characteristics. Only minimal residual disease was significantly different in the pediatric and adult ALL groups. Sex, leukocyte count, hemoglobin level and lactate dehydrogenase level were not significantly different between the two groups.
Immunophenotyping and FISH results
The expression of lineage markers in the two groups did not differ significantly. Table II shows that 82.6 and 14.7% of the adult ALL cases had B-lineage markers and T-lineage markers, respectively. In pediatric ALL cases, 81.2% had B-lineage markers and 12.1% had T-lineage markers.
Cytogenetically, genetic rearrangement, including the BCR-ABL fusion gene and MLL rearrangement, were detected in all adult patients. In adult patients, the rate of Ph chromosome positivity (Ph+) and MLL rearrangement was 38.6% (29/75) and 16.0% (12/75), respectively, and 1.3% (1/75) and 0% of patients were trisomy 4/10 and had the TEL-AML1 fusion gene, respectively. In pediatric ALL, 24.2% of patients (50/207) had MLL rearrangement and only 9.2% of patients (19/207) were Ph+, while 34.3% (71/207) and 7.7% (16/207) of patients were trisomy 4/10 or had the TEL-AML1 fusion gene, respectively. Fig. 1 depicts the FISH results. In Ph-negative and trisomy 4/10 negative patients, two red and two green particles were observed in the nucleus (Fig. 1A). In Ph-positive patients, there was one red, one green and one yellow particle in the nucleus (Fig. 1B). In MLL-negative patients, two yellow particles were observed in the nucleus (Fig. 1C). One red, one green and one yellow particle were observed in MLL-positive patients (Fig. 1D). Chromosome 4 amplification was observed as three red and two green particles (Fig. 1E); Chromosome 10 amplification resulted in two red and three green particles (Fig. 1F). In the TEL-AML1-negative sample, there are two red and two green particles (Fig. 1G); The TEL-AML1-positive sample usually presented with one red, one green and one yellow particle (Fig. 1H).
Prognosis analysis of cases with different chromosomes or immunophenotypes
Survival rates were calculated using the Kaplan-Meier method and compared with the log-rank test. The mean 3-year OS rate for the entire cohort was 59.5% (range, 56.3–62.7%), 74% (range, 70.7–77.3%) in the pediatric ALL group, and 18.8% (range, 13.6–24%) in the adult ALL group [hazard ratio (HR) =5.28; 95% confidence interval (CI), 3.59–7.78; P<0.001]. The 3-year EFS rate for the entire cohort was 50.6% (range, 47.4–53.8%), 62.8% (range, 59.1–66.5%) in the pediatric ALL group, and 16.5% (range, 12.0–21.0%) in the adult ALL group (HR=4.58; 95% CI, 3.22–6.52; P<0.001).
The multivariate analysis suggested that age, i.e., pediatric vs. adult patients, was most associated with OS (HR=4.44; P<0.001); Ph chromosome status (HR=2.71; P<0.001), MLL status (HR=1.65; P=0.020), TEL-AML1 fusion gene (HR=0.76; P=0.067) and white blood cell (WBC) level (HR=1.001; P=0.045) were independent prognostic factors of OS (Table III).
 | Table III.Multivariate analysis of prognostic factors of overall survival in acute lymphoblastic leukemia. |
In pediatric ALL cases, Ph chromosome (HR=3.56; P<0.001) and MLL status (HR=2.27; P=0.007) were independent prognostic factors of OS (Table IV). In adult ALL cases, Ph chromosome status (HR=2.21; P=0.016) and WBC level (HR=1.003; P=0.012) were independent prognostic factors of OS (Table V).
| Table IV.Multivariate analysis of prognostic factors of overall survival in pediatric acute lymphoblastic leukemia. |
| Table V.Multivariate analysis of prognostic factors of overall survival in adult acute lymphoblastic leukemia. |
Tables III–V demonstrate that Ph chromosome, MLL status and WBC level were independent prognostic factors of OS. Tables I and II indicate that MLL status and WBC level were not significantly different in the pediatric and adult ALL cases. This suggests that Ph+ is the primary reason for the worse prognosis in adult ALL than in pediatric ALL.
The prognosis of the two groups in the present study may differ so greatly as the pediatric and adult patients with ALL have different biological features. Prognostic analysis of all patients was stratified by the following biological features: i) In Ph-negative (Ph-) and Ph+ patients the 3-year OS rate was 68.5 vs. 16.9% (HR=4.21; P<0.001) and the 3-year EFS rate was 60.0 vs. 6.7% (HR=4.33; P<0.001); ii) in MLL-negative and -positive patients the 3-year OS rate was 62.5 vs. 51.8% (HR=1.34; P=0.112) and the 3-year EFS rate was 56.5 vs. 34.5% (HR=1.59; P=0.011); iii) in patients negative for trisomy 4/10 and TEL-AML1, trisomy 4-positive, trisomy 10-positive, TEL-AML1-positive patients, the 3-year OS rate was 52.6 vs. 60.6 vs. 82.6 vs. 87.2% (HR=0.587, P=0.004) and the 3-year EFS rate was 42.6 vs. 65.2 vs. 78.3 vs. 71.3% (HR=0.646; P=0.003); iv) in B lineage, T lineage or uncertain-lineage patients, the 3-year OS rate was 48.8 vs. 61.8 vs. 47.6% (HR=1.24; P=0.423) and the 3-year EFS rate was 35.8 vs. 53.7 vs. 40.0% (HR=1.29; P=0.131). Fig. 2 depicts the corresponding survival curves. Fig. 3 depicts the representative FACS results and morphological/histological images of B cell ALL, T cell ALL and atypical B-ALL patients. Patient 1 is a typical B-ALL patient. Immunologic cell markers of B-ALL show CD19, CD22, CD34 and HLA-DR are positive; CD3, CD7 and CD33 are negative. Wright's staining demonstrates the nuclei of B-ALL are regular and not indented or twisted. The lymphoblast has a high nuclear/cytoplasmic ratio. The POX staining is negative in all lymphoblasts of B-ALL. Patient 2 is a typical T-ALL patient. Immunologic cell markers of T-ALL indicate CD5, CD7, CD34 and CD38 are positive; CD19, CD20 and CD22 are negative. Wright's staining of T-ALL demonstrates that the cells are mostly larger than in B-ALL. There are more variations in cytologic features of the lymphoblast. The POX staining is negative in all lymphoblasts of T-ALL. Patient 3 is an atypical B-ALL patient accompanied by myelogenous markers. Immunologic cell markers of atypical ALL indicate CD10, CD19, CD22 and CD34 are positive; CD13 and CD33 are partially positive; CD3, CD7 and CD56 are negative. Wright's staining reveals that this cell type is larger than typical B-ALL. These lymphoblasts have also a high nuclear/cytoplasmic ratio. The POX staining is negative in almost all lymphoblasts.
Discussion
An estimated 6,000 new ALL cases (3,400 male and 2,600 female) are diagnosed annually in the USA (2). In China, this number is almost four times higher due to the larger population (18). ALL occurs in both children and adults but its incidence peaks between 2 and 5 years of age (3). The survival rate of childhood ALL is ~90%, but improvement is required for treatment in infants and adults (8).
ALL affects infants, children, adolescents, and adults. With current therapies, the vast majority of children with ALL are now long-term survivors (19). However, the same positive results have not been reported for adults with ALL (11). The present study confirms these results.
The cause of the differing prognosis of ALL is multifactorial, and largely includes genomic alterations, exogenous or endogenous exposure to environmental toxins and chance. The inferior prognosis of adult ALL is not fully understood but could be attributed, in part, to genetic susceptibility as compared to pediatric ALL (20,21). Significant differences were also detected in immunophenotype, i.e., Ph chromosome, trisomy 4 and 10, and the TEL-AML1 fusion gene, between pediatric and adult patients. The differences in Ph chromosome status may be a leading cause for the worse prognosis. It was also demonstrated that the OS or EFS of Ph+ patients were lower than that of Ph- patients. The same conclusion can be drawn from the multivariate analysis, in that Ph+ is an independent poor prognostic factor in ALL overall.
FISH is one of the most sensitive molecular methods for detecting genetic abnormalities such as chromosome translocation and submicroscopic chromosomal abnormalities with specific DNA probes (22). Even in non-mitotic cells or when cytogenetic studies are insufficient, FISH may detect cryptic or rare chromosomal rearrangement (23). However, conventional cytogenetic analysis cannot accurately detect non-dividing (interphase) cells, which represent the most important fraction of bone marrow cells (16). Therefore, FISH is more sensitive and time-efficient than traditional chromosomal tests, which was also confirmed previously (24). The inferior prognosis in adult ALL is attributed, in part, to the higher rate of Ph+ detected by FISH in adult patients as compared with pediatric patients.
The present retrospective study was designed predominantly to elucidate the relevance of the prognosis in pediatric and adult ALL and to define why the prognosis of these two groups differs, and to clarify whether it can be explained through the differing biological features detected by FISH. Significant differences were identified between the biological features and prognostic associations in adult and pediatric patients with ALL.
According to the present findings, the incidence of ALL decreases with age. A previous study of pediatric and adult patients with ALL identified no significant differences between sex, race/ethnic group and mean presenting WBC count (1).
Studies (25,26) have indicated that Ph+ ALL presents a dismal prognosis, representing an independent prognostic factor not only in pediatric patients, but also in adult patients. In the majority of patients with chronic myeloid leukemia, the ABL gene moves from chromosome 9 to the major breakpoint cluster region on chromosome 22. This translocation results in a 210-kDa fusion protein (p210). However, the ABL1 gene can also translocate to the minor breakpoint cluster region on chromosome 22, resulting in a 190-kDa fusion protein (p190) that occurs exclusively in ALL (27).
Ph+ ALL is characterized by poor response to the majority of chemotherapy combinations, short remission durations and poor survival rates (28). The findings suggested that the BCR-ABL fusion gene is an independent unfavorable prognostic factor for adult patients with ALL. Nevertheless, the development of allogeneic bone marrow transplantation and specific tyrosine kinase inhibitors for Ph+ ALL has potentially changed this (28).
In ALL, acute myeloid leukemia and therapy-associated leukemia, the MLL gene is rearranged with >70 partner genes and is located on the long arm of chromosome 11 (29). Reverse transcriptase-polymerase chain reaction previously revealed that this translocation was present in not only 40–50% of infants, but also in 2–3% of children and ~10% of adults with ALL (25). In the present study, 24.2% of pediatric patients and 16.0% of adult patients with ALL had MLL translocation, suggesting the high incidence rate of this location in China. Furthermore, the follow-up results indicate that the MLL gene is not associated with the poor prognosis of adult ALL, but that it is associated with poor prognosis of pediatric ALL.
The TEL-AML1 fusion gene, generated by the t(12;21)(p13;q22) chromosomal translocation, occurs in ~25% of cases of B cell precursor ALL. It is one of the most common forms of acute leukemia in children (30). The TEL gene is an important regulator in hematopoietic cell development, and the AML1 gene serves an important role in definitive embryonic hematopoiesis (25). The presence of the TEL-AML1 fusion protein in B-cell progenitors seems to be a hallmark of leukemic lymphoblasts, and leads to disordered early B-lineage lymphocyte development (26). The present findings indicated that the frequency of TEL-AML1 fusion was much higher in children than in adults, and is a favorable prognostic factor in patients with ALL. The EFS in TEL-AML1-positive patients was markedly longer than that of TEL-AML1-negative patients. A previous Pediatric Oncology Group study (31) revealed that trisomy 4 and 10 are strongly indicative of favorable prognosis, particularly in standard-risk B-precursor ALL. Although a number of genetic abnormalities are associated with clinical outcome, only a few are routinely used for treatment stratification (32,33). In the present study, pediatric patients with combined chromosome 4 and 10 trisomies appeared to have more prognostically favorable clinical features.
A limitation of the present study is that more sophisticated techniques were not used for comparing the disadvantages of FISH. Using second-generation sequencing technology, Zhao et al (34) previously revealed that 2,825 genes were upregulated and 1,952 were downregulated in the ALL group compared with the normal control group. Based on the digital gene expression profiling data, they investigated a further seven genes (WT1, RPS26, MSX1, CD70, HOXC4, HOXA5, OXC6) predominantly associated with immune cell differentiation, metabolic processes and programmed cell death. Although FISH is widely used in diagnosis and prognosis prediction of hematological malignancies, minimal residual disease (MRD) diagnostics has proven to be the strongest prognostic factor that may be used to guide treatment decisions. MRD techniques are required to be sensitive, accurate, reliable and fast. Recently developed high-throughput sequencing and next-generation (multidimensional) flow cytometry have been demonstrated to have greater potential means (35).
In conclusion, adult ALL has poorer prognosis than pediatric ALL. Ph+ status is associated with the high-risk features of increased age and is frequently observed and associated with unfavorable prognosis. Trisomies 4 and 10 are also associated with favorable prognosis but are not independent prognostic factors of ALL. Ph+ ALL is an independent prognostic factor of ALL that is frequently present in patients.
Acknowledgements
The author would like to thank the doctors of the Hematology Department of Xiangya Hospital for providing clinical data.
Funding
The present study was supported by the Hunan Provincial Scientific Research Project of Traditional Chinese Medicine (201798).
Availability of data and materials
All data generated or analyzed during this study are included in this published. No any other data available for supplementary materials.
Authors' contributions
The study presented here was performed as a collaboration between all authors. PC, YY, WW and HX performed the majority of the experiments. YH and PC made contributions to the design, data analysis and interpretation and drafting of the manuscript. PC, YY and WW collected and assembled the data. All authors gave their final approval for publication of the manuscript.
Ethics approval and consent to participate
The Xiangya Hospital Ethics Committee approved the present study (approval no. 201212478).
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
ALL |
acute lymphoblastic leukemia |
|
FISH |
fluorescence in situ hybridization |
|
MLL |
mixed lineage leukemia |
|
Ph |
Philadelphia |
|
TEL-AML1 |
translocation ETS leukemia-acute myeloid leukemia 1 |
|
OS |
overall survival |
|
EFS |
event-free survival |
|
HR |
hazard ratio |
|
CI |
confidence interval |
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