|Year : 2015 | Volume
| Issue : 1 | Page : 6-12
Clinical features and outcome of acute myeloid leukemia, a single institution experience in Saudi Arabia
Ahmed Al Faleh1, Abdullah Al-Quozi2, Ahmed Alaskar3, Mohsen Al Zahrani3
1 King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
2 Department of Pathology, King Abdulaziz Medical City, Ministry of National Guard, Riyadh; King Abdullah International Medical Research Center, Riyadh; King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
3 Division of Adult Hematology, King Abdulaziz Medical City, Ministry of National Guard, Riyadh; King Abdullah International Medical Research Center, Riyadh; King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
|Date of Web Publication||15-Apr-2015|
Mohsen Al Zahrani
King Saud Bin Abdulaziz University for Health Sciences
Source of Support: None, Conflict of Interest: None
Aim: Acute myeloid leukemia (AML) is a type of malignancy that is associated with a malignant alteration of normal hematopoietic stem cells in the bone marrow. The aim of this study was to study the demographics and pathological subtypes of AML, evaluate the response and outcome to different treatment modalities. Methods: This was a retrospective study of adult patients diagnosed with AML at King Abdulaziz Medical City - Riyadh, between 2006 and 2013. Data were retrieved from patients' files, electronic medical files and laboratory information system. Results: 91 patients were included in the study with a male dominance. M1 was the most common French-American-British subtype with 23 (32%) cases. Patients with intermediate-risk AML were the most common subgroup with 41 (48%) cases followed by high and low-risk subgroups, 29 (33%) and 16 (19%), respectively. 74 patients were treated with intensive chemotherapy, and 17 were on palliative chemotherapy or best supportive treatment. Remission rate was found to be 84% in patients who received induction chemotherapy while 41% of them relapsed. 93% of low-risk patients underwent complete remission (CR) compared to intermediate and high-risk patients (79% and 87% respectively), but it was not statistically significant (P = 0.4). The median follow-up was 19 months, with overall survival (OS) of 46% for all groups. The low-risk patients had the highest OS 57% compared to intermediate and high risk (52% and 36%, respectively), but it was not statistically significant (P = 0.3). 18 patients had been treated with allogeneic stem cell transplant and at a median follow-up of 17 months posttransplant the OS was 72%. Conclusion: This study shows M1 subtype to be the most common of AML in this population. In addition, the CR was better with similar survival rate as compared to other local and internationally published experiences. These results, albeit with its limitations, need to be confirmed in a prospective clinical trial or national disease registry.
Keywords: Acute myeloid leukemia, clinical and pathological features, Saudi Arabia, therapy outcome
|How to cite this article:|
Faleh AA, Al-Quozi A, Alaskar A, Zahrani MA. Clinical features and outcome of acute myeloid leukemia, a single institution experience in Saudi Arabia. J Appl Hematol 2015;6:6-12
|How to cite this URL:|
Faleh AA, Al-Quozi A, Alaskar A, Zahrani MA. Clinical features and outcome of acute myeloid leukemia, a single institution experience in Saudi Arabia. J Appl Hematol [serial online] 2015 [cited 2020 Aug 15];6:6-12. Available from: http://www.jahjournal.org/text.asp?2015/6/1/6/155171
| Introduction|| |
Acute myeloid leukemia (AML) is a type of malignancy that is associated with a malignant alteration of the normal hematopoietic stem cells (HPSC) in the bone marrow (BM). , The disease is characterized by an excessive proliferation of immature myeloid cell line, which leads to an accumulation of blast cells in the BM, blood, and organs such as spleen, liver, and rarely other organs. , This is often followed by a decline in the number of normal blood cells.  According to the World Health Organization (WHO) criteria, the diagnosis of AML is established by demonstrating more than 20% of the BM by leukemic myeloid blasts. 
Acute myeloid leukemia is considered one of the most common types of cancers in the US with an incidence rate of 5/100,000.  According to the latest Cancer Incidence Report in Saudi Arabia for the year of 2009, there were 619 documented new cases of adult leukemia, which accounts for 6.3% of all types of adult cancers. Leukemia is considered the third most common malignancy to affect males and the fifth in females. 164 out of 619 leukemia patients were AML patients.  AML is considered an age-related malignancy with a mean age of 70 years at diagnosis. 
During the 1970's, a classification of AML was established by a group of experts called "The French-American-British (FAB) classification of AML." The classification divided AML into eight subtypes from M0 to M7 based on the morphology of blast cells and the degree of maturation of those cells.  Recently, the WHO classification of AML was based mainly on the genetic changes, the etiologic factors of AML, and the morphologic classification of the disease. This new classification gives better insight for the causes of the disease, options of therapy and prognosis of AML. 
In most cases of AML, the underlying etiologies are unknown but there are well-known risk factors that increase the risk of developing AML. Exposure to chemicals such as benzene and radioactive materials can increase the risk of developing AML. AML also can develop as a secondary disease to other hematological disorders such as myelodysplastic syndrome (MDS) or myeloproliferative neoplasia, such as chronic myelocytic leukemia, or to previous exposure to chemotherapy or radiation therapy used for treating other malignancies. 
Around 50-60% of newly diagnosed patients with AML will have recurrent cytogenetic abnormalities, which can determine the disease prognosis.  Immunophenotype of malignant cells can also affect the outcome and response to treatment, e.g. patients with positive CD56 have a bad prognosis.  The most common antigens expressed in AML patients were CD13, CD33, CD117, and myeloperoxidase (MPO).  However, the most common lymphoid markers co-expressed aberrantly in patients with AML were CD7, CD2, CD19, and CD22.  Literature reported from Saudi Arabia revealed limited data about the clinical, pathological features and immunophenotypes of all subtypes of AML. Hence, this study was undertaken at our institution.
| Methods|| |
This study was conducted at King Abdulaziz Medical City (KAMC) in Riyadh. KAMC is a tertiary care center and JCI accredited with a bed capacity of more than 900 beds. It provides all types of care to all National Guard soldiers and their families, starting from primary health care up to tertiary specialized care. The oncology center was established in 2006 and has all oncology services including hematology and HPSC transplant service. This is a case series retrospective study that included all adult patients diagnosed with any AML subtypes from 2006 to 2013. Patients with mixed phenotypes leukemia were excluded. The data was retrieved manually from medical records, and electronically from the hospital electronic medical record system (Quadramed) for clinical data and the laboratory information system for flow cytometry and immunophenotype results. The data collected included patients' demographics data, genetic abnormalities of the disease, immunophenotypes and FAB pathologic subtypes of the disease, treatment protocol and response to treatment. Patients were classified according to the WHO criteria as low risk if they had t (15,17)/t (8,21)/t (16,16)/and inv. 16, or as intermediate risk if they had normal cytogenetic or cytogenetic abnormalities other than those seen in low-risk or high-risk categories and as high risk if they were secondary AML/complex cytogenetic/Monosomy 5 or 7 and relapsed refractory cases. One limitation of this classification was the lack of known AML molecular mutations in the risk stratification. The molecular genetic tests were either not done or not available for the majority of patients.
About 10-20 patients are diagnosed yearly with AML at KAMC, Riyadh, and the study included all adult patients with AML between the years 2006 and 2013. The whole population was studied, so no sampling was required. Data were entered into excel spreadsheets and then managed with SPSS (IBM SPSS version 16.0) using descriptive methods: Mean, standard deviation for numerical variables, percentages, frequencies for all categorical variables. Chi-square test was used for comparing the relapse, remission, and mortality among subgroups and Kaplan-Meier graph for determining the survival rate. The study was approved by the IRB at King Saud Bin Abdulaziz University for health sciences.
| Results|| |
There were 91 patients who qualified the inclusion criteria [Table 1]. There is a higher occurrence of the disease in male patients compared to female with a percentage of 58% and a mean age of 48.5 ± 20.6 years old for both genders. The median of presenting white blood cell in peripheral blood was 14 × 10 9 /L and blasts in BM were 65 × 10 9 /L. There were 72 patients with defined FAB subtypes, the most common FAB subtype was M1 in 23 patients (32%), followed by M2 in 19 patients (26%); there were no M6 among these AML patients. There were 86 patients who were risk stratified into low, intermediate, and high risk. Intermediate risk represented the majority of patients in this group with 41 patients (48%), low risk and high risk represented 16 patients (19%) and 29 patients (33%), results respectively. 5 patients had missing data, so we did not classify them. Primary AML accounted for 70 (76%) of all patients, secondary AML accounted for 21 (23%) and the most common cause for secondary AML was MDS.
In our group, the treatment was either curative (intensive chemotherapy) or noncurative (palliative) for newly diagnosed AML patients based on clinical decision. Intensive chemotherapy was given to 74 (81%) and 17 (19%) of patients were treated with palliative treatment only. Majority of patients received induction with 3 + 7 chemotherapy regimen (57 patients). The remaining patients in intensive therapy group were given different regimens such as (5 + 2) regimen, or high-dose cytarabine or acute promyelocytic leukemia induction regimen. In the palliative treatment group, different treatment options were given including low dose subcutaneous cytarabine in 4 patients, azacitidine in 1 patient and the remaining patients received only oral chemotherapy or best supportive measures. Furthermore, 18 (24%) patients had been treated with allogeneic stem cell transplant (SCT) either in first remission or second or third remission on disease relapse.
As shown in [Table 2], the remission rate among all patients and in each risk group or FAB subtypes. The complete remission (CR) rate after induction therapy in intensive chemotherapy group (≥1 cycle) was 62 (84%) patients (out of 74 patients). The remaining 12 patients (16%) were refractory to the induction therapy. The CR rate after one induction cycle was 73%. Low-risk patients had the highest CR rate compared to intermediate-risk and high-risk patients. The CR was 14 (93%) of the low-risk patients, 27 (79%) of the intermediate risk patients and 20 (87%) of the high-risk patients. However, the difference was not statistically significant (P = 0.4). The remission rate according to FAB subgroups was the following; patients with AML M3 as expected have the highest rate of complete response (100%), patients with AML M0 and M7 had the lowest rate of response 0% and 67%, respectively. However, the number of patients in each of these two subgroups is very small.
|Table 2: Remission rate in patients receiving intensive chemotherapy (N=74) |
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[Table 3] summarizes the relapse rate among all patients and in each risk group and FAB subtypes. There were 24 (41%) patients out of 59 patients, who had CR relapsed, 3 patients were not included due to incomplete data. The relapse rate according to different risk classes showed 5/12 (42%) low risk, 9/27 (33%) intermediate risk, and 10/19 (53%) high-risk patients had relapsed. Though the difference was not statistically significant (P = 0.4). [Table 3] shows the relapse rate in different FAB pathologic subtypes is as following: Nine out of 12 M1 patients, six out of 11 M2 patients, one out of 4 M3 patients, two out of 5 M4 patients, one out of 7 M5 patients, two out of 2 M7 patients had relapsed.
[Table 4] summarizes the survival among the population, risk groups, and FAB subtypes. After a median follow-up of 19 months, the overall survival (OS) was 40 (46%), 4 patients had missing data regarding the survival. There were 37 (53%) patients out of 70 survived in the intensive therapy group, and 3 (19%) in the palliative therapy group survived. Most of the deaths happened in the first 6 months after diagnosis and after a follow-up of 34 weeks there were not any deaths among the population [Figure 1]. High-risk patients had the poorest OS, 10 (36%) patients out of 28, 8 (57%) low-risk patients out of 14, and 21 (52%) intermediate risk patients out of 40 survived [Figure 2]. But there was no statistical significant difference among the subgroups, (P = 0.4). There were 18 (24%) of patients received SCT, 8 (44%) of them had relapsed and 13 (72%) had survived with median follow-up of 17 months [Table 5] and [Figure 3].
|Figure 3: Survival rate of patients who underwent allogeneic stem cell treatment|
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The flow cytometric panel for AML includes these markers (CD2, CD3, CD4, CD5, CD7, CD10, CD11b, CD11c, CD13, CD14, CD15, CD19, CD20, CD22, CD33, CD34, CD45, CD56, CD61, CD64, CD71, CD41, CD61a, CD117, HLA-DR, MPO, TdT, and cytoplasmic CD3%) [Table 6] and [Table 7]. CD13, CD33, and CD117 were the most common positive markers at diagnosis of all AML subtypes. CD2, CD4, CD7 were the most common aberrant lymphoid antigens expressed among AML cases. 2 patients did not have any data regarding the immunophenotypes.
| Discussion|| |
In this retrospective study, we were able to show some of the clinical and pathological features of AML in Saudi patients treated at a single center. In this small group of patients, discussion the classification according to the old FAB AML classification showed predominance of M1 and M2, followed by M4 and M5 with cases of M0, M6 and M7 representing only around 5%. Another local study, on AML patients showed that M4 and M5 are the dominant subtypes.  Regarding the risk stratification for our patients', the majority was in the intermediate risk group with most of those patients having normal cytogenetic. However, as has been shown recently in many studies those patients with normal cytogenetic can be further stratified into favorable or high risk based on presence or absence of certain molecular genetic aberrations. Patients with normal cytogenetic and with FLT3 mutation tend to have poor outcome and patients with mutated NPM or CEPBA in absence of FLT3 mutation tend to have a favorable outcome.  In our patients series, we were not able to sub-stratify patients with normal cytogenetic based on molecular aberrations because those tests were either not done, or the results are not available at the time of data collection.
The CR rate postinduction chemotherapy in our patient cohort was 73% after one induction cycle and 84% after one or more cycles. This high rate of CR in our patients population was seen in all risk groups. This response rate is higher than what has been reported from different clinical trials (60-70%).  Another local study on AML patients showed that 65% of the study population had first CR.  Possible explanations for the high response rate in our patients, we may have included some patients with favorable risk based on molecular genetic mutations, and usually those patients have high response rate. Another possible reason for this high complete response rate is inclusion of those who received multiple induction cycles, that is, more than one cycle and subsequently achieved a complete response. Furthermore, the OS rate was different than what is usually reported in other studies. The OS rate for low-risk group in our study is 57% and for high-risk group 36% this is in contrast to what has been reported of OS rate above 70% for low-risk AML and <20% for high-risk patients. , The allogeneic SCT group has a better OS (72%), suggesting that this procedure may improve the outcome of AML patients especially the high-risk group. The low-risk group had high remission rate but lower than expected OS rate and a possible explanation for this is the lack of utilizing molecular mutations in our classification for risk groups. It has been reported that patients with certain favorable cytogenetic changes may have a poor outcome such as t (8;21) in the presence of c-KIT mutation, and allogeneic hematopoietic SCT may improve the outcome in such cases. 
Abnormal blasts usually start to show morphological maturation, usually express precursor markers, including CD34, CD117. Each FAB subtypes has its own characteristic immunophenotypes, M3 subtype in particular has its own unique immunophenotype which can be differentiated from other FAB subtypes of AML. In this study, M3 cases were always negative for CD22, CD34, CD15, and HLA-DR. Our study showed that CD13, CD33, CD117, and MPO were the most common positive presenting antigens among M3 patients which is similar to another study findings.  Another study showed that CD45, CD33, CD13 were the most commonly expressed antigens.  CD2, CD4, CD7 were the most common apparent lymphoid antigens co-expressed in our AML cases. In addition to a local study, which showed CD9, CD7, CD19, CD4, and CD22, , our study showed CD2 was expressed in patients with M2 and M7 subtypes.
There were some limitations in our study including the retrospective nature of this study and a single center review. Furthermore, there were many patients included in the initial evaluation of treatment and response rate but had missing data. Finally, the molecular results of AML-related mutational analysis were not included in this group of patients for reasons mentioned previously.
| Conclusion|| |
This study shows M1 subtype to be the most common of AML in this population. In addition, the CR was better with similar survival rate as compared to other local and internationally published experiences. These results, albeit with its limitations, need to be confirmed in a prospective clinical trial or on a disease-based registry at the national level.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]
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