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HAEMATOLOGICAL MANIFESTATIONS AND FREQUENCY OF FAB SUBTYPES IN PATIENTS OF ACUTE MYELOID LEUKAEMIA: A SINGLE CENTER STUDY.

Byline: Muhammad Arif Sadiq, Ghassan Umair Shamshad, Nadir Ali, Eijaz Ghani, Suhaib Ahmed and Maham Arshad

Abstract

Objective: To determine the clinical/haematological manifestations and frequency of different subtypes of Acute Myeloid Leukaemia (AML) according to the French-American-British (FAB) classification.

Study Design: Descriptive study.

Place and Duration of Study: The study was carried out at haematology department of Armed Forces Institute of Pathology (AFIP), Rawalpindi from January 2011 to September 2012.

Material and Methods: Retrospective review of documents of patient diagnosed to have acute myeloid leukaemia on bone marrow aspiration was done. Patient's age, gender, major signs and symptoms at time of presentation and haematological parameters of peripheral blood and bone marrow were noted. The subtype of AML according to FAB classification was also documented. Data was entered and analyzed in SPSS 16.0.

Results: During the selected study duration acute myeloid leukaemia was diagnosed in 173 patients on bone marrow examination. Out of these 123 (71.1%) were males and 50 (28.9%) were females. Thirty (17.3%) of the patients fell in paediatric age group (less than 15 years) while the remaining 143 (82.7%) were in adult age category (greater than 15 years). The mean age of presentation was 9 years among paediatric patients and 44.5 years among adults. The overall mean age of both these two groups was 38.4 years (3-84 years). Fever (71.6%), generalized weakness (34.1%) and pallor (23.7%) were the three main complaints of the patients, followed by splenomegaly and lymphadenopathy. The mean total leukocyte count, haemoglobin and platelet count were 57.4 x 109/L, 7.9 g/dL and 54 x 109/L respectively. AML-M2 was found to be the most frequent FAB AML subtype among 72 (41.6%) paediatric and adult patients.

Conclusion: The main signs and symptoms of the patients of AML presenting to our centre were fever, generalized weakness and pallor. AML-M2 was found to be the most common FAB subtype among AML in children and adults.

Keywords: Acute myeloid leukemia, Fever French-American-British classification, Haematology, Pallor.

INTRODUCTION

Acute myeloid leukaemia (AML) is also known as acute non lymphocytic leukaemia or as acute myelogenous leukaemia. It is haemopoietic neoplasm involving clonal proliferation of precursors committed to the myeloid lineage, but with limited ability to differentiate further into mature cells resulting in accumulation of myeloid blasts and immature forms in blood, bone marrow and other tissues. AML comprises approximately 80% cases of acute leukaemia in adults and 20% cases in children1. The incidence of AML in adults over the age of 65 years is 30 times higher as compared to children2. The rapid proliferation and accumulation of blasts in bone marrow results in replacement of normal haemopoietic tissue with leukaemic cells leading to development of cytopenias.

The common symptoms with which patients present includes fever, progressive pallor, lethargy, shortness of breath, easy bruising or bleeding manifestations, infections, lymphadenopathy, hepatomegaly and splenomegaly3. There are two classification schemes employed to further subtype AML; the French-American-British (FAB) classification and World Health Organization (WHO) classification4,5. FAB classification of acute myeloid leukaemia is still commonly used in our country because of its good reproducibility and easy application even in under resourced laboratories6,7. According to FAB classification there must be greater than 30% myeloid blasts in the blood or bone marrow. It has further eight subtypes (Mo to M7) which are based on blast percentage, maturity level and lineage commitment of the myeloid precursors.

The response of AML to chemotherapy, its disease free survival and over all prognosis is heterogeneous. It depends upon variety of factors which include AML subtype, age, performance status, immunophenotyping and cytogenetics8,9. Keeping this in view the WHO proposed a classification which is regularly updated and incorporates cytogenetics, flow cytometry, molecular genetics, history of prior chemotherapy and evidence of dysplasia in the blast cells10. This classification provides more information regarding the prognosis and is therefore helpful in adopting appropriate treatment protocol.

In majority of the diagnostic centres in Pakistan, FAB classification is still widely used because it is based on morphology and cytochemical stains and does not require more advanced and costly equipment. However, with increasing awareness cytogenetics is being incorporated as an investigation tool to assess prognosis of AML patients. The objective of the study was to see clinical and haematological manifestations and frequency of different subtypes of acute myeloid leukaemia according to the FAB classification, as it is still easily understood by many physicians in our country.

MATERIAL AND METHODS

This descriptive study was carried out at the department of Haematology, Armed Forces

Table-1: Signs and symptoms of patients diagnosed with acute myeloid leukaemia(n=173).

Signs/Symptoms###Paediatric age###Adult age group Combined of both

###group f (%)###f (%)###age groups f (%)

Fever###28 (93.3%)###96 (67%)###124 (71.6%)

Generalized weakness###4 (13.3%)###55 (38.4%)###59 (34.1%)

Pallor###9 (30%)###32 (22.3%)###41 (23.7%)

Splenomegaly###9 (30%)###29 (20.2%)###38 (22%)

Lymphadenopathy###10 (33.3%)###24 (16.7%)###34 (19.6%)

Hepatomegaly###8 (26.6%)###25 (17.4%)###33 (19%)

Bleeding gums###4 (13.3%)###18 (12.5%)###22 (12.7%)

Aches and pain###3 (10%)###19 (13.2%)###22 (12.7%)

Bruising###8 (26.6%)###13 (9.1%)###21 (12.1%)

Breathlessness###3 (10%)###16 (11.2%)###19 (11%)

Gum hypertrophy###3 (10%)###11 (7.7%)###14 (8.1%)

Epistaxsis###4 (13.3%)###7 (4.89%)###11 (6.3%)

Bleeding per rectum###2 (6.6)###8 (5.6%)###10 (5.7%)

Bone pains###4 (13.3%)###2 (1.4%)###6 (3.5%)

Soft tissue swelling###1 (3.3%)###2 (1.39%)###3 (1.7%)

Table-2: Haematological parameters of patients of Acute myeloid leukaemia in the study according to age groups.

Haematological###Patient Group###Range###Mean###SD###p value

Parameters (units)

White blood cells###Paediatric###1.38 - 332###64.3###48.01###0.503

(109/L)###Adult###0.7 550.6###55.9###43.76

###Combined###0.7 550.6###57.4###44.41

Haemoglobin (g/dl)###Paediatric###3.2 10.7###7.3###0.95###0.275

###Adult###1.9 15.1###8.0###1.18

###Combined###1.9 15.1###7.9###1.15

Platelets (109/L)###Paediatric###2 -100###37.5###12.24###0.378

###Adult###3 436###58.1###30.32

###Combined###2 436###54.5###28.27

Institute of Pathology (AFIP), Rawalpindi. Approval from the Ethical Review Committee of AFIP was taken. A retrospective analysis of bone marrow documents from duration Jan 2011 to Sep 2012 was undertaken.

Bone marrow reports and the attached history sheets of 173 patients were thoroughly examined. All those patients who were diagnosed with AML on bone marrow aspiration were included in the study irrespective of their age and gender. However all those cases in which patients had previous history of myelodysplasia, aplastic anaemia, chronic myeloid leukaemia and primary myelofibrosis were excluded. Similarly patients receiving radiotherapy, chemotherapy and those who had relapsed after prior treatment for AML were also excluded from the study. The patients were divided into two age categories i.e. the paediatric age group (less than 15 years) which included infants, children and adolescents; and the adult age group (greater than 15 years).

Relevant history (duration of illness, symptoms and past medical/drug history) and positive findings in the physical examination of the patient from history sheet were documented. The total leukocyte count, haemoglobin, platelets, blast percentage in blood and bone marrow and FAB subtype of AML were also noted. The blood counts were done on automated haematology analyzer, Sysmex KX-21, while peripheral blood and bone marrow slides were stained with Leishman stain. The cytochemical stains used to determine lineage and subtypes of AML included Sudan Black B, Periodic acid Schiff and a-napthyl acetate esterase.

Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 16. Mean and Standard Deviation (SD) were calculated for quantitative variables like age, total leukocyte count (TLC), haemoglobin (Hb), platelets and blast cells in the peripheral blood and bone marrow. Qualitative variables like AML subtype, gender and clinical presentation of fever, splenomegaly, hepatomegaly, pallor, bleeding, bruising, bone pain, infection, lymphadenopathy and soft tissue swelling were expressed in frequency and percentages. Mann-Whitney U test was applied to compare variables between the two age groups. p value less than 0.05 was taken as significant.

RESULTS

Documents of 173 patients diagnosed to have acute myeloid leukemia were evaluated in the study. Out of these 123 (71.1%) were males and 50 (28.9%) were females; with a male to female ratio of 2.4:1. There were 30 (17.3%) patients in the paediatric age group and 143 (82.6%) in adult age group. The overall mean age of presentation in these patients was 38.39 years (SD=10.86) with a minimum age of 3 years and a maximum of 84 years. The mean age of presentation was 9 years among paediatric patients and 44.5 years among adults. The overall mean duration of illness at the time of presentation in both age groups was 45 days (SD=23) with a minimum of 7 days and maximum of 210 days. In the paediatric group the mean duration of illness at time of presentation was 58 days (SD=25), whereas in the adults it was 44 days (SD=22.5), a p value of 0.039.

The clinical features were diverse and non-specific; fever, generalized weakness and pallor were the most common clinical features in these patients (table-1).

Regarding haematological parameters, monocytopenia was seen in 5 (0.2%) patients, bicytopenia in 106 (61.2%) while 38 (21.9%) patients had pancytopenia at the time of presentation. The haematological parameters among the patients of AML are shown in table-2. No statistically significant difference was found between the haematological parameters of the two age groups of patients. The blast percentage in peripheral blood ranged from 5% to 94%, while in the bone marrow it was from 30% to 96%. The mean percentage of blasts in peripheral blood was 38% ( 10%) and in bone marrow was 68% ( 11.8%). AML-M2 was the most frequent FAB AML subtype among both paediatric and adult age groups; diagnosed in 72 (41.6%) of the patients followed by AML M4 in 31 (17.9%) patients. AML-M3 and its hypogranular/microgranular variant was diagnosed in 19 (10.9%) and 4 (2.3%) of the patients respectively.

Out of these AML-M3 patients only 5 (21.7%) were in paediatric group while rest of these were adults. None of the patient presenting during the study period was diagnosed with AML-M7. The frequency of AML subtypes according to FAB is shown in fig-1.

DISCUSSION

Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haemopoietic progenitor cells and the most common malignant myeloid disorder in adults. It arises within the bone marrow from myeloid precursor i.e. myeloblast, monoblast, erythroblast and megakaryoblast that accumulate in the marrow and interfere with production of blood cells. Over the course of last five years many laboratories and diagnostic centres have emerged that diagnose AML in the country, but still statistical data regarding our population with this leukaemia is deficient. As previously mentioned AML is further sub classified either according to FAB or WHO proposed classification schemes. The FAB classification was first introduced in 197611. According to this system; AML was divided into eight subtypes (Mo-M7). All subtypes can be diagnosed on the basis on morphology and cytochemistry except Mo, for which immunophenotyping is required12,13.

The WHO classification of acute myeloid leukaemia was introduced in 1997 and in this classification cytogenetic and molecular analysis was incorporated in 2003 and further revised in 2008. Inspite of its better correlation with prognosis, the WHO classification of AML is still not widely practiced in Pakistan because of financial constraints and expertise.

In this study patients' clinical and haematological manifestations were studied as they carry prognostic significance14. The mean age of presentation at time of illness was 38.4 years, which is almost identical to that determined by Kakepoto GN et al from Karachi in 200215. In a Saudi Arabian study the mean age at time of presentation in AML patients was determined to be 30 years16. AML is mainly a leukaemia of adults in our population as 82.6% of the patients fell in adult group, which conforms to the percentage reported Internationally1. However, the mean age of adult group in our study was 44.5 years whereas it is 70 years in the West.

The mean duration of illness at time of presentation was 45 days (SD=23). Children presented late as compared to adults as the presentation time 58 days (SD =25) and 44 days (SD=22.5) respectively. Possible explanations for this could be increased health consciousness of adults and more adaptive/flexible nature of body in children. The most common clinical features at presentation were fever (71.6%) and generalized weakness (34.1%). In an Indian study fever and generalized weakness were also found to be most common clinical feature17.

Kakepoto et al. also reported fever in 67.5% of AML patients, making it the commonest symptom15. Bone pains generally associated with acute lymphoblastic leukaemia were also seen in 6 (3.5%) of the patients.

AML-M2 was the most frequent AML subtype among both adult and pediatric age groups in our study. A similar study conducted in India in 2003 found AML-M2 to be the most frequent subtype both in adult and pediatric age groups15. Studies conducted by Asif MJ et al. and Butt FI et al. also reported that AML-M2 is the most common subtype among AML patients18,19. AML-M4 subtype was seen in 24 (16.7%) adults and in 5 (16.6%) of paediatric patients. This result was found consistent with the reported frequency (16-25%) in the literature1,20. AML-M4 Eo was found in 2 (1.15%) of the patients, both were adults. Similarly two of the adult patients had AML- Mo (1.15%) and no patient had AML-M7. Both patients of AML-Mo were Sudan black B negative and were diagnosed on immunophenotyping. They were CD117 positive. This result is consistent with a study conducted in Saudi Arabia, where AML-Mo was found in 1.7% patients21.

In our study 38 (21.96%) patients had pancytopenia, 106 (61.27%) patients had bicytopenia and 29 (16.77%) patients had normal counts in all cell lines. Acute leukaemia is one of the common causes of pancytopenia but patients can present without profound derangements of blood counts as shown in this study. Similarly, acute leukaemias presenting with high TLC i.e greater than 50 x 109/L carries bad prognosis3 and has been reported in 10-20% of the patients of AML22. In this study a total of 57 (32.9%) patients were found to have TLC greater than 50 x 109/L while 31 (17.9%) patients had TLC greater than 100 x 109/L. In a study by Oliveira LC et al. 27.2% of the patients had TLC greater than 50 x 109/L23 while in a very large study by Inaba H et al. 42.5% of the patients of AML had TLC greater than 100 x 109/L24.

Hyperleukocytosis is normally associated with ocular, cerebrovascular dysfunction and bleeding abnormalities, but only 8 of these patients had severe headache, while 2 had altered level of consciousness and one the patient had bleeding diathesis.

CONCLUSION

FAB AML-M2 is the most common subtype of acute myeloid leukaemia among children and adults in our population. The mean age of acute myeloid leukaemia in adults is considerably less in our population as compared to the West. Children normally present late to the hospital as compared to the adults. Fever and generalized weakness were the most common clinical features and so patients presenting with these complaints should be investigated thoroughly in order to rule out possibility of acute myeloid leukaemia.

CONFLICT OF INTEREST

This study has no conflict of interest to declare by any author.

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