|Year : 2017 | Volume
| Issue : 2 | Page : 41-48
Is the outcome of childhood acute myeloid leukemia with t(8;21) inferior in Saudi Arabia? A multicenter SAPHOS leukemia group study
Wasil Jastaniah1, Abdulrahman Alsultan2, Saad Al Daama3, Walid Ballourah4, Mohammad Bayoumy5, Faisal Al-Anzi6, Omar Al Shareef7, Mohammed Burhan Abrar8, Reem Al Sudairy9, Ibrahim Al Ghemlas10
1 Department of Pediatrics, Faculty of Medicine, Umm AlQura University, Makkah; Princess Noorah Oncology Center, King Saud Bin Abdulaziz University and King Abdulaziz Medical City, Jeddah, Saudi Arabia
2 Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
3 King Fahad Specialist Hospital, Dammam, Saudi Arabia
4 King Fahad Medical City, Riyadh, Saudi Arabia
5 King Faisal Specialist Hospital & Research Center Jeddah, Jeddah, Saudi Arabia
6 PrinceFaisalBin Bandar Cancer Center, Qaseem, Saudi Arabia
7 Prince Sultan Military Medical City, Saudi Arabia
8 Princess Noorah Oncology Center, King Saud Bin Abdulaziz University and King Abdulaziz Medical City, Jeddah, Saudi Arabia
9 Department of Pediatric Hematology/Oncology, King Abdullah Specialized Children’s Hospital, King Abdulaziz Medical City, Saudi Arabia
10 Faculty of Medicine, Alfaisal University; King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
|Date of Web Publication||17-Jul-2017|
Princess Noorah Oncology Center, King Saud Bin Abdulaziz University and King Abdulaziz Medical City, PO Box 9515 Box 9515, Jeddah 21423
Source of Support: None, Conflict of Interest: None
Background: Despite the confirmed favorable prognosis of childhood t(8;21) acute myeloid leukemia (AML), recent reports suggest heterogeneity in survival outcomes in this subtype of AML may be influenced by ethnicity. Therefore, we aimed to assess the outcome of childhood t(8;21) AML in an Arab population to evaluate if survival outcomes were inferior and determine the predictive relevance of additional cytogenetic abnormalities.
Methods: This multicenter retrospective study analyzed 175 de novo AML children of 14 years of age or younger consecutively diagnosed between January 2005 and December 2012. Survival outcomes were analyzed and patients with t(8;21) were stratified on the basis of karyotype into sole and additional cytogenetic groups.
Results: A total of 33 (18.9%) patients had t(8;21) AML. Complete remission (CR) was achieved in 31 (93.9%) patients. The 5-year overall survival, event-free survival, cumulative incidence of relapse (CIR), and remission death rates were 59.9 ± 9.2, 45.6 ± 9.1, 36.4, and 9.1%, respectively. Despite the administration of hematopoietic stem-cell-transplant salvage therapy in first relapse, five out of 11 (45.5%) relapsed patients died of disease. Subanalysis of sole vs. additional cytogenetic abnormalities revealed no significant difference in outcome.
Conclusion: In the present study, childhood t(8;21) AML was associated with inferior survival and resistance to salvage therapy compared to reports from international groups. The inferior outcomes were unrelated to additional cytogenetic abnormalities. Further detailed genetic studies are warranted to unmask the biological and clinical differences between racial/ethnic groups. Given the high CR rate of childhood t(8;21) AML, further modification of postremission therapy to improve the CIR rate is needed.
Keywords: AML, child, core binding factor, ethnicity, leukemia, prognosis, t(8;21)
|How to cite this article:|
Jastaniah W, Alsultan A, Al Daama S, Ballourah W, Bayoumy M, Al-Anzi F, Al Shareef O, Abrar MB, Al Sudairy R, Al Ghemlas I. Is the outcome of childhood acute myeloid leukemia with t(8;21) inferior in Saudi Arabia? A multicenter SAPHOS leukemia group study. J Appl Hematol 2017;8:41-8
|How to cite this URL:|
Jastaniah W, Alsultan A, Al Daama S, Ballourah W, Bayoumy M, Al-Anzi F, Al Shareef O, Abrar MB, Al Sudairy R, Al Ghemlas I. Is the outcome of childhood acute myeloid leukemia with t(8;21) inferior in Saudi Arabia? A multicenter SAPHOS leukemia group study. J Appl Hematol [serial online] 2017 [cited 2018 Jul 22];8:41-8. Available from: http://www.jahjournal.org/text.asp?2017/8/2/41/210827
| Introduction|| |
Core binding factor (CBF) acute myeloid leukemia (AML), defined by the presence of t(8;21)(q22;q22) or inv(16)(p13.1q22)/t(16;16)(p13.1;q22), is the most common recurring cytogenetic abnormality, representing approximately 25% of cytogenetic subtypes, in childhood de novo AML., The overall survival (OS) rate of 91% for t(8;21) and 92% for inv(16) in childhood CBF AML has been confirmed by the Medial Research Council (MRC) and the Berlin–Frankfurt–Munster (BFM) study groups., Therefore, childhood AML patients with these cytogenetic abnormalities are treated similarly, considered to have favorable prognosis, and are not candidates for hematopoietic stem cell transplant (HSCT) in first complete remission (CR1).
In contrast, studies in adults demonstrated that patients with t(8;21) and inv(16) manifest not only biological differences, as expressed by different gene profiling, but also distinct morphological, immunophenotypic, and clinical behavior., It has been shown that coexistence of variable clinical or biological features, such as presence of secondary cytogenetic aberrations, molecular abnormalities, coexpression of antigens, and/or white blood cell count (WBC) may affect the outcome of CBF AML, in particular t(8;21)., In addition, t(8;21) and inv(16) differ with regards to response to induction and salvage treatments. These differences suggest that adult patients with t(8;21) and inv(16) should be considered as separate entities from the clinical standpoint.
As outcomes between childhood and adult AML differ, there are indications that age-dependent factors in CBF AML also exist. Recent studies have shown that biological differences between children with t(8;21) and inv(16) exist., However, the impact of clinical factors and secondary cytogenetic abnormalities on outcome of childhood CBF AML remains uncertain. Recently, the international BFM group reported the impact of additional cytogenetic aberrations and treatment regimens on outcome of childhood t(8;21) AML. The study concluded that additional cytogenetic abnormalities involving deletions of chromosome arm 9q (del(9q)) or gain of chromosome 4 might be associated with inferior outcomes. Furthermore, treatment regimen influenced the outcome.
The Children’s Oncology Group (COG) reported the impact of ethnicity on survival in children with AML. Furthermore, the influence of race/ethnicity on patient outcomes in t(8;21) AML has been reported., In one study, non-whites had inferior remission and OS rates compared to whites when certain secondary cytogenetic abnormalities were present, and in a meta-analysis of the prognostic significance of KIT mutations in CBF AML, race/ethnicity had a significant effect on outcomes in patients with t(8;21)., The underlying reasons for these findings are uncertain but may be related to variability in access to care and compliance, distinct ethnic genetic background, or differences in treatment used. Therefore, further studies in different ethnic populations are required to define the distinct genotypic patterns and the associated clinical behavior of this unique yet heterogenous subtype of CBF AML to optimize treatment outcomes of childhood t(8;21) AML.
In light of the above, the Saudi Arabian Pediatric Hematology Oncology Society (SAPHOS) initiated this multicenter collaborative study. The purpose of the study was: first, to determine whether the clinical outcome of childhood AML with t(8;21) in an Arab population is inferior to outcomes reported by major leukemia cooperative groups. Second, assess the impact of clinical factors and the presence of additional cytogenetic aberrations on outcomes. To the best of our knowledge, the clinical characteristics and outcomes of childhood t(8;21) AML in Arab populations have not been extensively studied. Therefore, this study will contribute to the medical literature in several ways: first, it describes the demographics and outcomes of childhood t(8;21) AML in Saudi Arabia. Second, it evaluates the impact of additional cytogenetic aberrations and treatment protocol on outcomes in childhood t(8;21) AML to assess compatibility/incompatibility with international studies and unmask the prognostic factors that may lead to disparity. Third, it explores the variability in clinical characteristics and outcome of childhood t(8;21) AML in an ethnic population that has not been comprehensively studied, therefore, bridging some of the knowledge gap that exists in the medical literature.
| Materials and Methods|| |
This retrospective multicenter collaborative study involved nine institutions in Saudi Arabia and was approved by the ethics committees of each participating institution. The Sanad children’s cancer support association funded the study. The pediatric age group in Saudi Arabian institutions is defined as children of 14 years or younger. Therefore, patients of age 14 years or younger consecutively diagnosed with de novo AML between January 2005 and December 2012 were evaluated. Data were collected using Research Electronic Data Capture tools hosted and stored in a secure Microsoft SQL database at SAPHOS central office. Study data included: age, gender, WBC, central nervous system (CNS) status, French–American–British (FAB) classification, immunophenotype, genetic abnormalities at diagnosis, treatment protocol, response, events, survival, and follow-up.
Reports of cytogenetics and/or fluorescent in situ hybridization when performed on pretreatment bone marrow (BM) samples or peripheral blood (PB) specimens were reviewed. The International System for Human Cytogenetic Nomenclature was used to describe karyotypes. A diagnosis of t(8;21) AML was made if t(8;21)(q22;22) and/or RUNX1–RUNX1T1 was detected. Patients with missing or incomplete karyotype were excluded.
Patients were treated in each center on the basis of one of the standard regimens of the following protocols: the United Kingdom MRC-AML12, the COG-AAML0531, and the Pediatric Oncology Group (POG8498) treatment protocols.,, All protocols used intensive cytarabine-based therapy; however, the MRC-AML12 and the COG-AAML0531 used higher anthracycline and etoposide doses compared to the POG8498 protocol as summarized in [Table 1]. In addition, the cumulative cytarabine and etoposide doses are relatively higher in the COG-AAML0531 protocol. Except for patients with FLT3/ITD mutations who received HSCT in CR1, the indication for HSCT was limited to patients with relapsed/refractory disease if a suitable human leukocyte antigen (HLA)-matched donor was found.
|Table 1: Comparison of chemotherapeutic agents used and cumulative doses by protocol|
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Events evaluated as end points were: CR, cumulative incidence of relapse (CIR), event-free survival (EFS), and OS. CR was defined as less than 5% of the blasts in the BM by the end of induction and induction failure as 5% blasts or more in the BM or detection of circulating blasts in the PB, following two courses of conventional induction chemotherapy, and early death as death within 42 days from the date of diagnosis. CIR was calculated from the date of CR until hematological relapse taking into account death in CR as competing risk. OS was defined as the time elapsed from date of diagnosis to time of death due to any cause or time of last follow-up and EFS as the time from date of diagnosis to last follow-up or first adverse event (induction failure, relapse, second malignancy, or death due to any cause). The Kaplan–Meier method was used to estimate the probability of survival and the log-rank test to determine statistical significance. Time-dependent Cox model was used to check the log-rank test assumption of constant hazard ratio over time. Cox proportional hazard models were used to determine potential predictors of survival. Predictive factors found to be significant at P < 0.10 in the univariate analysis were considered for inclusion in the multivariate analysis. All other tests were considered statistically significant if P < 0.05.
| Results|| |
Of the 175 consecutive patients diagnosed with de novo AML and had complete data, 33 (18.9%) patients had t(8;21), and the clinical features are shown in [Table 2]. The median age was 7.2 years and the male:female ratio was 1.4:1. Majority of patients presented with low WBC of 20 × 109/L or less, CNS involvement was observed in five (15.2%) patients, and the most frequent FAB subtype was M2 (72.7%). Aberrant CD56 coexpression was reported in nine out of 20 (45.0%) tested cases. The percentage of cytogenetic abnormalities is shown in [Table 3]. The majority of patients (60.6%) had t(8;21) as the sole abnormality, whereas 39.4% had an additional abnormality. The most frequent additional cytogenetic abnormality was loss of a sex chromosome (LOS) followed by del(9q). None of our t(8;21) patients had gain of chromosome 4, and two had FLT3/ITD mutations.
|Table 2: Clinical characteristics of de novo childhood acute myeloid leukemia patients with t(8;21) acute myeloid leukemia|
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The COG-AAML0531 protocol was used in 10 (30.3%), the MRC-AML12 in 13 (39.4%), and the POG8498 in 10 (30.3%) patients. Thus, there was an even distribution of patients between protocols. Ten patients received HSCT as salvage therapy, and two patients with FLT3/ITD received HSCT in CR1.
CR was achieved in 31 (93.9%) of patients. The CR rates by protocol were 90, 92.3, and 100% for the COG-AAML0531, MRC-AML12, and POG8498, respectively. Eleven out of 33 (33.3%) patients relapsed (two in the COG-AAML0531, five in the MRC-AML12, and four in the POG8498 protocol). The 5-year CIR was 36.4%. Twelve patients died, of which, seven (21.2%) were disease-related, three (9.1%) death in remission, and two (6%) early death. The 5-year EFS and OS were 45.6 ± 9.1 and 59.9 ± 9.2%, respectively [Figure 1]. Patients with CD56 coexpression vs. those with no coexpression had a 5-year EFS rate of 11.1 ± 10.5 vs. 27.3 ± 13.4% (P = 0.492) and OS rate of 11.1 ± 10.5 vs. 36.4 ± 14.5% (P = 0.182), respectively. Subanalysis to assess the influence of cytogenetic aberrations on survival outcomes was conducted. The EFS was 40.0 ± 11.0 vs. 50.5 ± 17.8% (P = 0.368) for t(8;21) patients with sole vs. those with additional cytogenetic aberrations, respectively. Similarly, the OS was 54.0 ± 11.4 vs. 76.2 ± 12.1% (P = 0.462), respectively. Thus, no differences in survival outcomes between patients with sole vs. additional cytogenetic abnormalities were observed. Further subanalysis by specific cytogenetic abnormalities was not possible due to the limited number of patients in each subcategory. However, LOS was associated with a higher trend of OS and EFS rates: 80.0 ± 17.9 and 62.5 ± 21.3%, respectively, compared to the OS and EFS of patients with other additional cytogenetic aberrations: 56.1 ± 10.1 and 42.4 ± 9.9%, respectively. In addition, all patients with del(9q) survived and the two patients with FLT3/ITD mutations survived with no events.
|Figure 1: The 5-year overall survival and event-free survival of childhood t(8;21) acute myeloid leukemia|
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Survival analysis by protocol revealed 5-year EFS of 46.7 ± 21.4% for COG-AAML0531, 44.0 ± 14.3% for MRC-AML12, and 40.0 ± 15.5% for POG8498 (P = 0.813). Similarly, the 5-year OS for the corresponding protocols were 78.8 ± 13.4, 60.6 ± 13.8, and 50.0 ± 15.8%, respectively (P = 0.586). Therefore, no differences in survival rates were noted between patients treated with different protocols. Furthermore, covariates known to influence survival including: age, gender, WBC, CNS involvement, CD56 coexpression, cytogenetic abnormalities, and treatment protocol were examined in the Cox model. However, none were found to be significant.
| Discussion|| |
We retrospectively evaluated the clinical characteristics and outcome of childhood t(8;21) AML, with the aim to determine if the outcome is inferior compared to that reported by major leukemia cooperative groups. In the present study, t(8;21) represented 18.9% of cytogenetic subtypes in childhood de novo AML, this frequency is higher than the 12 to 15% reported in children by major leukemia cooperative groups in Western countries but lower than the 32% reported by the Japanese childhood AML cooperative study.,, This observation is consistent with studies that reported geographic heterogeneity in the prevalence of t(8;21) with increased frequency in Asian compared to European and North American countries., This heterogeneity in prevalence between different geographic regions suggests uneven environmental exposures that may be closely associated with the development of childhood AML and/or inherent biological differences as a result of ethnic diversity that may produce variations in AML biology or responses to therapy. Despite this, the median age of t(8;21) patients was 7.2 years with a male predominance which is consistent with that reported by the international BFM study. Other studies have reported female predominance., Majority of patients had a low WBC at presentation; however, CNS involvement was observed in approximately 15%, which is higher than the 7.8% reported by the international BFM study group. The most common FAB type was M2 in our study, which is consistent with other studies. Therefore, the demographic features showed similarities and differences when compared to reports by other groups.,,,,,,,,,,, However, none of the demographic features in the present study were associated with outcome.
The CR rate of 93.9% was similar to the 91.5% reported in the international BFM study, 98% in the MRC-AML trial, 95.6% from the COG-AAML0531 study, and 94 to 100% from the AML-BFM studies.,,,, In contrast, the EFS rate of 45.6 ± 9.1% was lower than those reported by major leukemia cooperative groups.,,,,,,, Similarly, the OS rate of 59.9 ± 9.2% was inferior compared to other studies [Table 4].,,,,,,, Furthermore, the CIR was 36.4% compared to 30.3% in the COG-AAML0531, 19% in the MRC-AML12, 12% in AML-BFM trial, and 26% in the international BFM study.,,,, Despite comparable CR rates, childhood t(8;21) AML outcomes in our study were inferior compared to those reported by major leukemia cooperative groups. This could be attributed to variability in access to care and supportive care, distinct ethnic genetic background, or differences in the treatment protocols used.
|Table 4: Comparison of selected childhood acute myeloid leukemia studies that report survival rates of t(8;21) acute myeloid leukemia|
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Access to care and supportive care have been reported to influence the outcome of childhood AML. Furthermore, the outcome of AML in developing countries has been reported to be inferior to those reported in developed countries.,, However, Saudi Arabia, a high-income resource-rich developing country, offers supportive care services that are comparable to those observed in developed countries and free access to cancer care to all Saudi nationals. The level of supportive care delivered in cancer centers in Saudi Arabia has significantly improved. For example, in a study from Saudi Arabia, improved supportive care measures resulted in a reduction in the toxic mortality rates in childhood AML patients that were comparable to rates reported by major leukemia cooperative groups. Furthermore, the treatment of childhood AML requires hospitalization during all phases of therapy limiting compliance-related differences. Therefore, socioeconomic factors were unlikely to have influenced the differences in outcomes observed between studies. In the present study, remission death was 9.1%, which is higher than the range of 2 to 6% reported by the COG-AAML0531 and the AML-BFM studies.,, However, this rate is within the 6 to 10% remission death reported in the MRC-AML trials and the 7.9% in the international BFM study., Furthermore, patients in the present study were treated with five or more courses of chemotherapy on the basis of the standard regimen used in the original protocol. Therefore, given the observed toxic mortality rate in this study but excellent CR rate, it may be appropriate to reduce the intensity of postremission therapy for childhood t(8;21) AML. The MRC-AML12 trial showed no difference in the survival or relapse rate between patients treated with five vs. four courses of chemotherapy. Therefore, further modification of postremission therapy may help reduce remission death.
Race/ethnicity has been reported to influence the outcome of patients with t(8;21)., Furthermore, in a Japanese study, childhood t(8;21) AML with KIT mutations was associated with inferior outcomes than those with wild-type KIT. In contrast, no difference in outcome between pediatric patients with and without KIT mutations in an American and a Taiwanese series was observed, whereas in a Chinese study, KIT mutation was associated with an adverse survival outcome in adult t(8;21) AML but not in children.,, These differences could be related to biological differences in leukemia cells harboring variable cooperating genetic abnormalities that may influence the clinical behavior and outcome of patients with AML in different geographic regions, of different race/ethnicity, and/or of different age groups.,,, However, in the present study, only two patients were tested for KIT mutations and hadwild-type KIT, whereas the remaining patients were not tested; therefore, subanalysis by KIT mutation was not possible.
Studies have shown that additional genetic aberrations might impact the outcome in t(8;21) AML., The percentage of patients with additional cytogenetic abnormalities in the present study (39.4%) was comparable to the 31 to 68% range reported by other studies.,,,, Similarly, LOS and del(9q) were the most frequent additional cytogenetic aberrations, which is consistent with reports by other groups.,,,,,,, Although the number of specific secondary cytogenetic abnormalities was too small to examine the prognostic effect on outcome in our study, the presence of additional cytogenetic abnormalities did not influence outcomes when compared to sole t(8;21). Furthermore, patients with LOS abnormalities had a trend of superior OS and EFS, whereas patients with del(9q) and FLT3/ITD mutations all survived without events. Our results were consistent with those of von Neuhoff et al. and Creutzig et al., which showed no impact of additional cytogenetic abnormalities on outcome and inferior survival rates for t(8;21) as a single abnormality but a higher survival rate for t(8;21) with LOS. In the von Neuhoff et al. study, all four patients with del(9q) survived. Furthermore, a study that included pediatric and adult patients with t(8;21) showed better outcome in patients with chromosome 9 abnormalities. These findings are consistent with the observations in our study. In contrast, a recent pediatric study showed that del(9q) and gain of chromosome 4 negatively affected outcome; and the LOS abnormality has been reported to have an inferior outcome in another study., Therefore, the impact of specific secondary genetic abnormalities in childhood t(8;21) remains uncertain. However, the fact that pediatric t(8;21) patients with sole abnormalities fared worse in our study, and other studies suggest that underlying molecular abnormalities may need to be unmasked to help target improvement in outcome. Studies investigating the impact of mutations in the tyrosine kinase pathway in pediatric t(8;21) AML have produced inconsistent results.[6-8,26-28] Recently, a comprehensive mutational profiling study combining both adult and pediatric patients showed a negative synergistic effect on outcome for patients with t(8;21) who had at least one tyrosine kinase pathway mutation associated with at least one additional mutation in a chromatin modifier or cohesion gene. Our study was limited by the fact that detailed genetic testing was not performed, as, to date, genetic profiling is not considered standard practice in the clinical setting. Therefore, further large-scale studies are required to optimize a targeted approach to childhood t(8;21) AML.
The prognostic significance of CD56 overexpression in AML patients with t(8;21) has been reported in many adult studies., Recently, a meta-analysis indicated that in AML with t(8;21) translocation, CD56 overexpression was significantly associated with shorter survival and increased risk of relapse but no effect on CR rate. However, studies on the prognostic impact of CD56 coexpression in pediatric AML are limited and unclear. In the present study, CD56 coexpression was associated with an inferior trend in 5-year OS and EFS. However, this did not reach statistical significance. Given the limited number of CD56 tested patients, no meaningful conclusion can be made.
Patients were analyzed on the basis of the treatment protocols received. The CR, CIR, EFS, and OS rates by protocol were not significantly different. These observations are in contrast to other studies that have shown the impact of protocol on outcome in patients with t(8;21).,,, For example, in one study, intensifying cytarabine and mitoxantrone therapy in pediatric t(8;21) AML significantly improved survival and reduced relapse rate. Furthermore, in an adult study, the outcome of t(8;21) patients in first relapse improved when gemtuzumab ozogamicin (GO) was received before transplant. Although the protocols used in our study varied in the cumulative doses used as summarized in [Table 1], all protocols utilized intensive cytarabine-based therapy. This may explain the comparable outcomes observed between protocols in our study. Therefore, as the cumulative anthracycline dose in current pediatric AML protocols reached its maximum, alternative targeted therapeutic approaches are needed to improve the outcome of patients with t(8;21). The addition of GO to standard therapy in the COG-AAML0531 study significantly reduced relapse in low-risk patients from 30.3 to 19.7%. However, postremission toxic mortality increased from 1.8 to 7.5% among GO recipients. Therefore, with the current successful remission induction rates in childhood t(8;21) AML, further modification of postremission therapy to reduce relapse risk and improve toxic mortality is warranted to optimize outcomes for childhood t(8;21) AML.
| Conclusion|| |
The survival outcomes of childhood t(8;21) AML in Saudi Arabia was inferior compared to results from major leukemia cooperative groups. The inferior survival was unrelated to variability in demographic features, the presence of additional cytogenetic aberrations, access to care, or socioeconomic factors. Furthermore, no significant difference in outcome by protocol was detected. Therefore, the impact of ethnicity/geography on outcome of childhood t(8;21) could not be excluded and further detailed genetic studies are warranted to unmask the biological and clinical differences between racial/ethnic groups. In the present study, relapsed childhood t(8;21) AML was associated with resistance to salvage therapy. It may, therefore, be appropriate to incorporate minimal residual disease (MRD) measurement in childhood t(8;21) AML to intensify postremission therapy for those with persistent MRD and reduce intensity of postremission therapy for those with complete response to decrease toxic mortality rates. However, given the limitations of the present study, there is a need for prospective multinational/multiethnic collaborative efforts to improve our understanding and treatment of childhood t(8;21) AML.
Financial support and sponsorship
This study was funded through a research grant fund by Sanad Children’s Cancer Support Association, a nonprofit charitable association funding Children’s Cancer Research in Saudi Arabia. The authors would like to acknowledge Sanad for their support in funding this study.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]