|Year : 2020 | Volume
| Issue : 1 | Page : 18-22
Clinical profile, cytogenetics and treatment outcomes of adult acute myeloid leukemia
MS Namratha Udupa1, K Govind Babu1, MC Suresh Babu1, KC Lakshmaiah1, D Lokanatha1, A Linu Jacob1, KN Lokesh1, LK Rajeev1, AH Rudresh1, Lakshmi Devi2
1 Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
2 Department of Pathology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
|Date of Submission||18-Oct-2016|
|Date of Acceptance||24-Feb-2018|
|Date of Web Publication||24-Oct-2018|
M S Namratha Udupa
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru . 560 029, Karnataka
Source of Support: None, Conflict of Interest: None
Introduction and Aims: Acute myeloid leukemia (AML) in adults has poor prognosis. The epidemiologic profile of patients varies greatly in different geographic locations and so do the cytogenetic abnormalities and the FAB subtype of the AML. We intended to study the clinical profile, cytogenetics, and outcomes with standard of care treatment on our population in India.
Methods: This was a retrospective study with systematic review of 203 case records. Primary objectives were to know the demographic profile of AML, prevalence of various FAB subtypes, cytogenetic abnormalities, and treatment outcomes at our center, which is a referral center of oncology. Two treatment outcomes considered in study for patients of AML were achievement of remission status of the bone marrow postintensive induction chemotherapy and sustenance of the remission for 6 months, once remission is achieved. Secondary objective was to study these outcomes in non-M3 AML in relation to cytogenetics.
Results: Median age was 39 years. The most common FAB subtype observed was AML M2. About 65.6% patients achieved complete remission (CR), and 42.4% patients could sustain it for next 6 months. Cytogenetics correlated with prognosis but not age.
Conclusions: Our population differs from the Western population regarding lower age, lower prevalence of adverse cytogenetics, and higher prevalence of favorable cytogenetic abnormalities. Cytogenetics had a good correlation with CR rates after chemotherapy as well as its sustenance.
Keywords: Acute myeloid leukemia, clinical profile, cytogenetics, treatment outcomes
|How to cite this article:|
Namratha Udupa M S, Babu K G, Suresh Babu M C, Lakshmaiah K C, Lokanatha D, Jacob A L, Lokesh K N, Rajeev L K, Rudresh A H, Devi L. Clinical profile, cytogenetics and treatment outcomes of adult acute myeloid leukemia. J Can Res Ther 2020;16:18-22
|How to cite this URL:|
Namratha Udupa M S, Babu K G, Suresh Babu M C, Lakshmaiah K C, Lokanatha D, Jacob A L, Lokesh K N, Rajeev L K, Rudresh A H, Devi L. Clinical profile, cytogenetics and treatment outcomes of adult acute myeloid leukemia. J Can Res Ther [serial online] 2020 [cited 2020 Jun 2];16:18-22. Available from: http://www.cancerjournal.net/text.asp?2020/16/1/18/243471
| > Introduction|| |
Acute myeloid leukemia (AML) in adults has a sinister prognosis. It comprises 80% of acute leukemia in adults and 20% in children. It has been shown that the disease is curable in 5%–15% of elderly (>60 years) and 35%–40% of adults under 60 years of age with intensive chemotherapy. It has a poor median survival of 10 months in those who are not offered chemotherapy due to lack of fitness and various other reasons. The incidence of AML is lower in black population (3.86/100,000) as compared to the Western population (4.62/100,000).
The epidemiologic profile of patients varies greatly in different geographic locations, and so do the cytogenetic abnormalities and the FAB subtype of the AML. Cytochemistry and immunophenotyping are commonly done investigations for establishing the diagnosis. Immunophenotyping which undoubtedly is an important diagnostic tool in AML has an established role in situ ations where only bone marrow morphology does not suffice-in cases of diagnostic dilemma, to differentiate myeloblasts from lymphoblasts, in cases of leukemia with mixed lineage and also in assessment of minimal residual disease. Conventional cytogenetics is an important tool in prognostication of patients.,, With this background, we intended to study the clinical profile, cytogenetics, and outcomes with standard of care treatment on our population in India.
| > Materials and Methods|| |
This was a retrospective study with systematic review of 203 case records of patients of AML at a tertiary center of oncology from January 1, 2013, to December 31, 2014. Inclusion criterion was all patients of AML above 15 years of age, diagnosed at our center and exclusion criteria were patients who were partially/previously treated at other centers and patients with relapsed disease. Primary objectives were to know the demographic profile of AML, prevalence of various FAB subtypes, cytogenetic abnormalities and treatment outcomes at our center, which is a referral center of oncology. Two treatment outcomes considered in study for patients of AML were the achievement of remission status of the bone marrow postintensive induction chemotherapy, and sustenance of the remission for 6 months, once remission is achieved. A secondary objective was to study these outcomes in non-M3 AML in relation to cytogenetics.
Details noted down were the demographic profile, peripheral smear details, bone marrow examination details, type of induction regimen used, marrow status postinduction and whether there was sustenance of remission for 6 months following remission. Complete remission (CR) was defined as blast percentage of <5% in the bone marrow and peripheral blood neutrophil recovery (>1 × 109/l) and platelet recovery (>100 × 109/l). Conventional cytogenetics with analysis of a minimum of 20 metaphases with any specific abnormality occurring in at least two metaphases for its characterization was done. Nomenclature was based on guidelines by the International System for human Cytogenetics Nomenclature 2009. The three risk groups were taken as defined by the European Leukemia Net (ELN) 2009 guidelines-favorable with t (8,21), inv 16, t (16,16), or t (15,17); Intermediate with normal karyotype or t (9,11) and adverse with inv (3), t (3,3), t (6,9), t (v, 11), −5 or del (5q); −7, abnl (17p); complex karyotype anomalies. Complex karyotype was defined as presence of 3 or more anomalies in the absence of WHO-defined recurring cytogenetic abnormalities of AML.
Patients who were fit for intensive chemotherapy and non-AML M3 were administered the standard induction chemotherapy with 3 days of daunorubicin at an infusional dose of 60 mg/m2 over 3 h for the first 3 days and cytarabine at an infusional dose of 100 mg/m2 over 24 h for 7 days. Six of the 125 patients were not able to complete 7 days of induction, 4 of them received for 6 days, and 2 for 5 days due to rapid deterioration in performance status. Consolidation regimen as per our institute protocol was 3 g/m2 of cytarabine over 3 h, twice daily for 3 days. 3–4 such cycles were administered. None of these patients were given allo transplantation as most of our patients have logistic issues and are from poor financial background. Patients of AML M3 were all in poor performance status and as per institutional protocol received induction with oral all-trans retinoic acid at a dose of 45 mg/m2 and infusional arsenic trioxide at a dose of 0.15 mg/kg till complete hematological remission. A total of thirty patients received only best-supportive care due to poor performance status or untreatable comorbidities or both, and they were excluded from the assessment of considered outcomes. Hypomethylating agents-decitabine and azacitidine were used in 25 patients who were not fit to receive intensive chemotherapy, and they were also excluded from the assessment of considered outcomes [Table 1].
The statistical analysis was carried out using Statistical Package for Social Sciences (version 22.0 for Windows SPSS Inc., Chicago, IL, USA). It was done by Pearson Chi-square method. Means and medians were calculated for parametric and nonparametric data, respectively, as applicable.
| > Results|| |
Among the 203 patients studied 99 (48.7%) were female and 104 (51.3%) were male. Median age was 39 years (16–82 years). The presenting symptom in majority of our patients was fever seen in 151 patients (74.3%) followed by easy fatigability in 116 patients (57.1%). Lymphadenopathy in cervical and axillary nodes was observed in 75 patients (36.9%). Hepatosplenomegaly was found in 54 patients (26.6%). Bleeding into mucocutaneous areas was seen in 42 (20.6%) patients, mostly in cases with acute promyelocytic leukemia. Most of the patients had a combination of these symptoms. Gum swelling as a presenting feature was seen in seven patients (3.4%), mostly in those with M4, M5, and M2 subtypes. Mean duration of symptoms before reporting to the hospital was 2 weeks [Table 2].
The most common FAB subtype observed was AML M2 (43.3%) followed by M4 (22.7%), M3 (11.8%), M1 (7.4%), 5b (6.4%), M0 (3.4%), M6 (2.5%), M5a (2%), and M7 (0.5%) [Figure 1].
Cytogenetics yielded results in 173 (85.2%) patients. The most common cytogenetics observed was normal karyotype seen in 60 (34.6%) patients followed by abnormalities such as t (8,21) in 36 (20.8%), and inv 16 in 31 (17.9%) patients. As per ELN 2009 guidelines, patients were risk stratified into three risk groups-favorable, intermediate, and adverse groups. Complex karyotype with more than three anomalies was present in four patients. There were 88 (50.8%) patients in the favorable risk group, 66 (38.1%) patients in the intermediate, and 19 (10.98%) patients in the adverse risk groups [Table 3].
Two outcomes considered in the group which was administered intensive chemotherapy were achievement of CR postintensive induction chemotherapy and the sustenance of the remission for 6 months postinduction chemotherapy. Of the 125 patients treated with intensive induction chemotherapy, a total of 82 (65.6%) patients succeeded in achievement of CR and 53 (42.4%) patients could sustain it for the next 6 months [Table 1]. Rest of the patients could not be included into analysis in view poor compliance to treatment, low follow-up rates, and heterogeneity of salvage treatments. The corresponding rates were 91.3% and 82.6%, respectively, in AML M3. All-cause mortality in the group of receiving intensive chemotherapy was 18.4%, and that in the group of AML M3 was 8.69%. AML-M3 has been excluded from the analysis of the other non M3-AML and is separately analyzed.
Cytogenetics and treatment outcomes
Cytogenetics and complete remission status postintensive induction chemotherapy
As age did not show any correlation with this outcome, statistical adjustment for age was not required. The risk groups of AML were compared with the two outcomes. There was a statistically significant difference in the rates of achievement of remission status in bone marrow postinduction in the risk groups-favorable (84.4%), intermediate (74.5%), and adverse (57.9%) with P = 0.028 [Figure 2].
|Figure 2: Cytogenetics and complete remission status postintensive induction chemotherapy|
Click here to view
Cytogenetics and complete remission status sustenance for 6 months postintensive induction chemotherapy
As age did not show association with this outcome also, statistical adjustment for age was not required. Cytogenetics was also a significant prognostic indicator in predicting sustenance of the CR status over next 6 months with a statistically significant P = 0.003 [Figure 3].
|Figure 3: Cytogenetics and complete remission status sustenance for 6 months postintensive induction chemotherapy|
Click here to view
| > Discussion|| |
AML is a group of diseases with vast heterogeneity and geographical diversity regarding clinical and cytogenetic profile. The median age of incidence of the disease in our study was 39 years, which is lower compared to an age of 51.4 years in Japanese and 50.7 years in Australian population. Gender distribution in this study was grossly equal-104 males: 99 females (1.05:1) in contrast to a few studies where the disease has male preponderance.,
The most common presenting symptom in our patients was fever (74.3%) as compared to fatigue in 82% of patients in a study by Ghosh et al . Excessive fatigue was present in 57.1% of our patients mostly along with fever and uncommonly as an isolated presenting symptom. In the same study, lymphadenopathy and hepatosplenomegaly were observed in 36.2% and 26.2% of patients, respectively, which is comparable to the incidences observed in our study. Gum swelling as one of the presenting symptom was seen in 3.4% of our patients.
The most common FAB subtype of AML observed in this series was AML M2, seen in 43.3% of the patients. This was higher than the reported incidence of 21.6%–42% in various other studies. AML M4 occurrence (22.7%) was almost similar to the incidence in other studies (17%–39%). Similarly, the occurrence of AML M3 (11.8%) was at par with that of its occurrence in other studies stating values from 5% to 12%.,,,
Normal karyotype (34.68%), t (8, 21) (20.8%), and inv 16 (17.9%) were the most common cytogenetics observed in this study. Thus, core binding factor (CBF) AMLs in our study constituted 42.2% of all the cytogenetics, which is higher than that observed in a few other studies. In the same study, it is stated that the preponderance of harboring CBF AML s comes down with age. The occurrence of more CBF AMLs is probably explained by the predominance of the younger age in our study population. Further, the two most common abnormalities in CBF AMLs of t (8,21) and inv 16 composed of 38.7% in contrast to 12% in a large series on Western population by Grimwade et al . Normal karyotype in our study (34.68%) is lesser compared to 48% in another study by Byrd et al . and 41% as per another series. The incidence of AMLs with adverse cytogenetics was only 10.98% which was surprisingly far less compared to an incidence around 45% in an article by Kumar.
Age in our study did not show correlation with both of the considered outcomes, probably due to its negative skewing in distribution. Of the patients treated with intensive induction regimen, 91.4% were under 64 years of age. It may also be due to the fact that most of the patients (78%) did not have any age-related comorbidities. In those non-M3 AML patients treated with intensive induction, CR rates were 84.4%, 74.5%, and 57.9% in the favorable, intermediate and adverse risk groups and thus cytogenetics was a statistically significant strong prognosticator of CR. The CR rate in the favorable group was slightly lower than the CR rate (86%–95%) obtained in the CALGB 8461 study. Similarly, the CR rate in the adverse risk groups was also lower compared to the CR rate of 13%–57% in the same study. However, the intermediate group had results comparable to that in the same study (68%–75%). This could probably be attributed to the higher dose (200 mg/m2) of cytarabine in that study compared to the dose (100 mg/m2) used in the present study. Also as certain patients were offered a second induction as compared to only one patient in our study, our CR rates could be slightly lower. We did not use the higher dose as our patients do not usually tolerate higher dose with myelosuppression-induced febrile neutropenia being the dose-limiting toxicity.
We could not get molecular markers of prognostication for all the patients with normal cytogenetics-NPM1, CEBPA, and FLT3-ITD, in view of the financial constraints in our patients. We had reports of only five patients, and hence, it was excluded from the analysis. All three markers were negative in three patients, FLT3-ITD positive in 1 and CEBPA was positive in the other patient.
| > Conclusions|| |
Our population has a much lower median age of incidence of AML. Our population differs from the Western population regarding lower age, lower prevalence of adverse cytogenetics and higher prevalence of favorable cytogenetic abnormalities. The CR rates after treatment were marginally lower, probably due to the lower doses of cytarabine used and refrainment at using second induction chemotherapy in view of poorer tolerability and toxicity issues. Cytogenetics had a good correlation with CR rates after chemotherapy as well as its sustenance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Weinstein H. Acute myeloid leukemia. In: Pui CH, editor. Childhood Leukemias, UK: Cambridge University Press; 1999.
Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N
Engl J Med 2015;373:1136-52.
Howladder N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, et al
. Cancer Statistics Review, 1975-2012. Bethesda: National Cancer Institute; 2015.
Ghosh S, Shinde SC, Kumaran GS, Sapre RS, Dhond SR, Badrinath Y, et al.
Haematologic and immunophenotypic profile of acute myeloid leukemia: An experience of tata memorial hospital. Indian J Cancer 2003;40:71-6.
] [Full text]
Meng CY, Noor PJ, Ismail A, Ahid MF, Zakaria Z. Cytogenetic profile of de novo
acute myeloid leukemia patients in Malaysia. Int J Biomed Sci 2013;9:26-32.
Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, et al.
Refinement of cytogenetic classification in acute myeloid leukemia: Determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom medical research council trials. Blood 2010;116:354-65.
Wang ML, Bailey NG. Acute myeloid leukemia genetics: Risk stratification and implications for therapy. Arch Pathol Lab Med 2015;139:1215-23.
de Greef GE, van Putten WL, Boogaerts M, Huijgens PC, Verdonck LF, Vellenga E, et al.
Criteria for defining a complete remission in acute myeloid leukaemia revisited. An analysis of patients treated in HOVON-SAKK co-operative group studies. Br J Haematol 2005;128:184-91.
Shaffer LG, Slovak ML, Campbell LJ; Nomenclature ISCoHC. ISCN 2009: An International System for Human Cytogenetic Nomenclature. Basel: Karger; 2009.
Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, et al.
Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European leukemiaNet. Blood 2010;115:453-74.
Mrózek K, Marcucci G, Nicolet D, Maharry KS, Becker H, Whitman SP, et al.
Prognostic significance of the European leukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol 2012;30:4515-23.
Nakase K, Bradstock K, Sartor M, Gottlieb D, Byth K, Kita K, et al.
Geographic heterogeneity of cellular characteristics of acute myeloid leukemia: A comparative study of Australian and Japanese adult cases. Leukemia 2000;14:163-8.
Roberts GT, Spence DG, Padmos MA, Sheth KV, Clink H, Ernst P, et al.
Morphologic immunophenotypic and cytogenetic patterns of adult acute myeloid leukemia in Saudi Arabia. Leuk Res 1992;16:181-90.
Udayakumar AM, Pathare AV, Al-Kindi S, Khan H, Rehmen JU, Zia F, et al.
Cytogenetic, morphological, and immunophenotypic patterns in omani patients with de novo
acute myeloid leukemia. Cancer Genet Cytogenet 2007;177:89-94.
Paschka P, Döhner K. Core-binding factor acute myeloid leukemia: Can we improve on HiDAC consolidation? Hematology Am Soc Hematol Educ Program 2013;2013:209-19.
Byrd JC, Mrózek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, et al.
Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo
acute myeloid leukemia: Results from cancer and leukemia group B (CALGB 8461). Blood 2002;100:4325-36.
Kumar CC. Genetic abnormalities and challenges in the treatment of acute myeloid leukemia. Genes Cancer 2011;2:95-107.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]