|Year : 2015 | Volume
| Issue : 1 | Page : 35-39
Favorable subset of acute myeloid leukemia with translocation 8;21: An elusive experience
Nusrat Bashir Khan1, Yasir Bashir Khan2, Farooq Ahmad Ganie3, Syed Sajad Geelani2, Mohamed Aleem Jan2, Sheikh Aejaz Aziz2
1 Department of Pathology, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
2 Department of Clinical Hematology, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
3 Department of Cardiovascular and Thoracic Surgery, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
|Date of Web Publication||8-Dec-2014|
Farooq Ahmad Ganie
Department of Cardiovascular and Thoracic Surgery, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Soura, Srinagar, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Background: Risk stratification is critical in the management of acute myeloid leukemia (AML) and among the favorable subset translocations known, 8;21 seems elusive in our clinical practice as regards the response remission status. This led us to review our patients retrospectively to highlight this ambiguity. Patients and Methods: A retrospective study was carried out on a total of 20 patients positive for translocation (8;21) and negative for FLT3 and NPM gene mutation. These patients were treated with standard AML treatment protocols. Post induction day 14 and day 28 assessments were done. Four patients died during induction chemotherapy and all the remaining patients were in remission. Subsequently, these patients were subjected to consolidation chemotherapy. Results: Out of total of 16 (80%) survivors, 10 (50%) could not maintain the remission status on a mean follow-up of 6 months and were treated with a different induction protocol. After the second induction, all patients were in remission at day 28, but this remission again was short lasting (<3 months). Conclusion: One needs to be careful in treatment of AML with translocation (8;21) and this should not be taken as a single criterion for treatment of these patients. These patients should be subjected to additional somatic mutation analysis before final risk stratification.
Keywords: Acute myeloid leukemia, chemotherapy, remission
|How to cite this article:|
Khan NB, Khan YB, Ganie FA, Geelani SS, Jan MA, Aziz SA. Favorable subset of acute myeloid leukemia with translocation 8;21: An elusive experience. Muller J Med Sci Res 2015;6:35-9
|How to cite this URL:|
Khan NB, Khan YB, Ganie FA, Geelani SS, Jan MA, Aziz SA. Favorable subset of acute myeloid leukemia with translocation 8;21: An elusive experience. Muller J Med Sci Res [serial online] 2015 [cited 2019 Dec 13];6:35-9. Available from: http://www.mjmsr.net/text.asp?2015/6/1/35/146422
| Introduction|| |
Pathobiology of acute leukemia conceptualizes the existence of leukemic stem cell having unlimited self division and clonal production of leukemic progenitors and lack of normal hematopoietic differentiation. Leukemogenic mutations and clonal cytogenetic abnormalities are novel and prognosticate leukemias, and are critical in targeted therapeutics for individualization of treatment. Secondary mutations of Kras, Nras, and KIT are common in such patients.  The t(8;21)(q22;q22) translocation is one of the most frequent balanced chromosomal translocations found in acute myeloid leukemia (AML), occurring in approximately 8% of patients with de novo AML. , AML carrying the t(8;21) translocation exhibits some specific characteristics. This AML subset is morphologically associated with the French-American-British (FAB) AML-M2 subtype.  With the sequential advances made in AML induction regimens, patients with the t(8;21) karyotype have consistently been reported to have a higher complete remission (CR) rate compared with AML patients with other cytogenetic abnormalities. ,,,,, The core binding factor (CBF) AMLs result from translocations involving either RUNX1 or CBFB. In t(8;21) AML, RUNX1T1 (formerly known as CBFA2T3 or ETO) on chromosome 8 is fused with RUNX1 on chromosome 21.  In inv(16) AMLs, CBFB located at 16q22 is fused to the MYH11 gene located at 16p13.  Both translocations are thought to lead to leukemia by creating fusion products that are dominant negative inhibitors of normal myeloid differentiation. , In addition to sharing a similar pathogenetic mechanism, the CBF leukemia shares the characteristics of sensitivity to high-dose cytarabine (HDAC) treatment and has a relatively favorable prognosis compared with most other forms of adult AML. , The incidence of CBF-AML decreases with age, and is it represents less than 5% in those of age 60 years and above. , The elderly patients with CBF-AML have higher CR rates and longer survival times , compared with patients who have other types of AML. However, the outcome seems inferior to that of younger patients. ,,, Appelbaum et al.,  reported a 5-year estimated probability of overall survival (OS) of 48% in the whole population compared with 22% for patients older than 65 years.
| Patients and Methods|| |
This retrospective study was carried out on data collected from a total of 20 patients. Diagnosis was based on morphology characterization as per FAB classification  and flow cytometric analysis of bone marrow samples simultaneously. All karyotypes were interpreted according to the International System for Human Cytogenetic Nomenclature.  All our patients had the translocation 8;21.
All these patients were enrolled for standard chemotherapy regimen  wherein they received daunorubicin 60 mg/m 2 daily for first 3 days of chemotherapy and a continuous infusion of cytarabine at a dose of 200 mg/m 2 daily for 7 days. All patients were subjected to bone marrow examination on day 14, and those with a blast count more than 20% and cellularity more than 30% received 2;5 re-induction. Remission status was looked into on day 28 of chemotherapy in all the patients and if in remission, consolidation chemotherapy was started with HDAC at a dose of 3 g/m 2 on days 1, 3, and 5 for a total of four doses given 4-6 weeks apart. A re-induction chemotherapy with MTC (mitoxantrone, topotecan, and cytarabine) was administered to those who relapsed after consolidation with HDAC.
Definition of Clinical End Points
CR was defined as recovery of morphologically normal bone marrow (BM) and normal blood counts (i.e. neutrophils 1500/l and platelets 100,000/l), and no circulating leukemic blasts or evidence of extramedullary leukemia. Relapse was defined by 5% BM blasts, circulating leukemic blasts, or development of extramedullary leukemia.  OS was measured from the date of the study until the date of death or the date last known alive. Cumulative incidence of relapse (CIR) was measured only in patients who achieved a CR, from the date of CR to the date of relapse, death, or date last known alive, in which death in CR was considered a competing risk.
| Results|| |
Patient Characteristics at Diagnosis
All patients enrolled in this study were positive for translocation 8;21 and negative for FLT3 and NPM gene mutation. Among the patients, 12 (60%) were females and the remaining 8 (40%) were males. The mean age at diagnosis was 31.55 years. Six (30%) had morphological diagnosis of AML M1 and the remaining 14 (70%) were AML M2. None of the patients had any additional chromosomal abnormality.
Remission Status at the End of Induction Given in [Table 1]
All patients were in remission on day 14 of induction. Subsequently, 4 (20%) patients died in the third and fourth week of induction. At day 28, all survivors were in remission. So, in brief, 80% of the total and 100% among survivors were in remission immediately after induction chemotherapy.
Follow-up Status Post 4 th HDAC High-Dose Cytarabine
Immediately after completion of consolidation chemotherapy, all patients were in remission and continued to be in remission till the 5 th month post-consolidation when 10 (62.50%) relapsed and were treated with an MTC induction protocol.
Follow-up Post MTC Re-Induction
Immediately after MTC re-induction, all those who received MTC went into remission on day 28. Unfortunately, all of them relapsed within a mean duration of 8 weeks.
On subsequent follow-up of these patients, it was observed that those patients who were in remission at 12 months continued to be in remission at the end of this study, i.e. at 24 months. [Table 2] describes the clinical characteristics at diagnosis in studied patients.
| Discussion|| |
Previous studies have evaluated the prognostic and clinical characteristics of patients with t(8;21) and inv(16) AML, ,, but rarely there had been a study highlighting the poor outcome in this subset. It becomes very difficult to defend this clinical observation, but one should not hesitate to project this observation for want of a scientific reason. The treatment of AML is influenced by genetic markers, and recent studies have identified an increasing number of recurrent somatic mutations in AML patients, including mutations in TET2, , ASXL1, , IDH1 and IDH2, , DNMT3A,, and PHF6.  In addition, several of these newly diagnosed abnormalities have been shown to have prognostic importance in AML. Despite an initial response to induction/consolidation therapy, most AML patients relapse with disease that is broadly resistant to chemotherapy. A recent study provided the first large-scale insight into the genetics of relapsed AML wherein whole-genome sequencing of eight AML patients with relapsed AML was performed.  In each case, the AML genome at diagnosis and at relapse was sequenced and compared with the genome sequencing of matched normal tissue. Instead of restricting themselves to somatic events in coding regions, the investigators validated all candidate somatic events in each tumor, allowing for a much greater number of mutations to be used to track the evolution from diagnosis to relapse. Two clear patterns emerged when the mutations found at diagnosis and at relapse were analyzed. In one model, a confounding clone and multiple subclones clonally derived from this confounding clone were extant at diagnosis. After chemotherapy, the residual cells from one of the minor subclones expanded to become the dominant clone at relapse. This clone also carried additional mutations that were only observed at relapse. Clonal progression from diagnosis to relapse of this nature was seen in five of the eight patients in this study. In the other three patients, the evolution from diagnosis to relapse was much simpler, i.e. the dominant clone at the time of diagnosis simply acquired more mutations at relapse. In all patients, there existed a confounding clone that was not ablated by chemotherapy and was still persistent at relapse. Prospective identification of this clone at diagnosis would be of utmost clinical utility. The identification of mutations at diagnosis could serve as a tool for minimal residual disease measurement and allow for the deployment of therapies to eradicate residual clones after induction and consolidation therapy.
The most widely used induction regimen for AML has remained the same for more than 30 years: Three daily doses of daunorubicin (or its equivalent, anthracycline) at 45 mg/m 2 and infusion of cytarabine for 7 days. As noted earlier, the ECOG E1900 trial evaluated the use of anthracycline dose intensification during induction therapy. A total of 657 patients between the ages of 17 and 60 years with de novo AML were randomized to receive either the standard dose of 45 mg/m 2 daunorubicin or a higher dose of 90 mg/m 2 . The higher-dose cohort achieved a higher rate of complete remission and an increase in OS. The benefit of high-dose daunorubicin was restricted to those less than 50 years age and to those AML patients with cytogenetically defined favorable or intermediate risk. A subsequent study investigating high-dose versus low-dose daunorubicin in AML patients younger than 60 years of age reported findings similar to the ECOG E1900 trial.  A similar study in patients older than 60 years  observed an increased rate of complete remission in the higher-dose cohort (64% vs. 54%). However, prolonged OS was only seen in patients under the age of 65 years and those with CBF-positive leukemia.
Unfortunately, these previous studies did not include prospective mutational profiling to identify the biomarkers that could be used to delineate the subsets of patients who would most benefit from intensified chemotherapy. This is particularly important given the heterogeneity in outcome in these clinical trials. A subsequent post-hoc analysis of mutational status, induction therapy, and outcome in the E1900 cohort revealed that high-dose daunorubicin improved the outcomes markedly in patients with DNMT3A mutations.  Patients with mutant DNMT3A receiving high-dose daunorubicin had similar outcome to DNMT3A wild-type patients receiving high-dose or standard-dose daunorubicin. Patients with Mixed lineage leukemia (MLL) fusions or with NPM1 mutations also had improved OS when treated with high-dose daunorubicin. Interestingly, MLL fusions were mutually exclusive with DNMT3A and NPM1 mutations, suggesting a potential shared biologic mechanism explaining the sensitivity to daunorubicin.
Thus, we conclude that since our patients were not subjected to somatic mutation analysis, proper risk stratification could not be done only on the basis of karyotype and, in addition, no subsequent dose adjustments were made during induction chemotherapy depending upon such mutation analysis. The possibility of confounding clone and subclones becoming dominant when these patients relapsed could not also be ruled out.
| Conclusion|| |
AML patients should be subjected to additional somatic mutation analysis before final risk stratification. We should try to risk-stratify our patients beyond cytogenetics. In addition, their mutational analysis should also guide us in deciding the drug dosage during induction chemotherapy. Last but not least, in cases that relapse, the possibility of confounding clone and subclone becoming dominant clone should also be considered and mutations at diagnosis and subsequent acquired mutations could help us for minimal residual disease measurement.
| References|| |
Kebriaei P, Champlin R, de Lima M, Estey E. Management of acute leukemias. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, editors. DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology. 9 th
ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. p. 1928-54.
Trujillo JM, Cork A, Ahearn MJ, Youness EL, McCredie KB. Hematologic and cytologic characterization of 8/21 translocation acute granulocytic leukemia. Blood 1979;53:695-706.
Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, et al
. The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998;92:2322-33.
Acute myelogenous leukemia with an 8;21 translocation. A report on 148 cases from the Groupe Français de Cytogénétique Hématologique. Cancer Genet Cytogenet 1990;44:169-79.
Dastugue N, Payen C, Lafage-Pochitaloff M, Bernard P, Leroux D, Huguet-Rigal F, et al
. Prognostic significance of karyotype in de novo
adult acute myeloid leukemia. Leukemia 1995;9:1491-8.
Stasi R, Del Poeta G, Masi M, Tribalto M, Venditti A, Papa G, et al
. Incidence of chromosome abnormalities and clinical significance of karyotype in de novo
acute myeloid leukemia. Cancer Genet Cytogenet 1993;67:28-34.
Schiffer CA, Lee EJ, Tomiyasu T, Wiernik PH, Testa JR. Prognostic impact of cytogenetic abnormalities in patients with de novo
acute nonlymphocytic leukemia. Blood 1989;73:263-70.
Mrózek K, Heinonen K, de la Chapelle A, Bloomfield CD. Clinical significance of cytogenetics in acute myeloid leukemia. Semin Oncol 1997;24:17-31.
Berger R, Bernheim A, Ochoa-Noguera ME, Daniel MT, Valensi F, Sigaux F, et al
. Prognostic significance of chromosomal abnormalities in acute nonlymphocytic leukemia: A study of 343 patients. Cancer Genet Cytogenet 1987;28:293-9.
Keating MJ, Smith TL, Kantarjian H, Cork A, Walters R, Trujillo JM, et al
. Cytogenetic pattern in acute myelogenous leukemia: A major reproducible determinant of outcome. Leukemia 1988;2:403-12.
Licht JD. AML1 and the AML1-ETO fusion protein in the pathogenesis of t(8;21) AML. Oncogene 2001;20:5660-79.
Liu P, Tarlé SA, Hajra A, Claxton DF, Marlton P, Freedman M, et al
. Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. Science 1993;261:1041-4.
Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer 2002;2:502-13.
Downing JR. The core-binding factor leukemias: Lessons learned from murine models. Curr Opin Genet Dev 2003;13:48-54.
Byrd JC, Ruppert AS, Mrózek K, Carroll AJ, Edwards CG, Arthur DC, et al
. Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): Results from CALGB 8461. J Clin Oncol 2004;22:1087-94.
Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, et al
. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: A Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000;96:4075-83.
Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ, et al
.; Medical Research Council Adult Leukemia Working Party. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): Analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001;98:1312-20.
Vey N, Coso D, Bardou VJ, Stoppa AM, Braud AC, Bouabdallah R, et al
. The benefit of induction chemotherapy in patients age > or = 75 years. Cancer 2004;101:325-31.
Schoch C, Kern W, Schnittger S, Büchner T, Hiddemann W, Haferlach T. The influence of age on prognosis of de novo
acute myeloid leukemia differs according to cytogenetic subgroups. Haematologica 2004;89:1082-90.
Farag SS, Archer KJ, Mrózek K, Ruppert AS, Carroll AJ, Vardiman JW, et al
.; Cancer and Leukemia Group B 8461. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: Results from Cancer and Leukemia Group B 8461. Blood 2006;108:63-73.
Appelbaum FR, Kopecky KJ, Tallman MS, Slovak ML, Gundacker HM, Kim HT, et al
. The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations. Br J Haematol 2006;135:165-73.
Marcucci G, Mrózek K, Ruppert AS, Maharry K, Kolitz JE, Moore JO, et al
. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): A Cancer and Leukemia Group B study. J Clin Oncol 2005;23:5705-17.
Delaunay J, Vey N, Leblanc T, Fenaux P, Rigal-Huguet F, Witz F, et al
.; French Acute Myeloid Leukemia Intergroup; Groupe Ouest-Est des Leucémies Aiguës Myéoblastiques; Leucémies Aiguës Myéoblastiques de l'Enfant; Acute Leukemia French Association; Bordeaux-Grenoble-Marseille-Toulouse Cooperative Groups. Prognosis of inv(16)/t(16;16) acute myeloid leukemia (AML): A survey of 110 cases from the French AML Intergroup. Blood 2003;102:462-9.
Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292-302.
ISCN. Mitelman F, editor. ISCN 1995: An International System for Human Cytogenetic Nomenclature. Basel, Switzerland: Karger; 1995. p. 21- 3.
Fauci A, Braunwald E, Kasper D, Hauser S, Longo D, Jameson J, et al
. Harrisons Principles of Internal Medicine. Vol. 1. 17 th
ed. McGraw-Hill; 2008. p. 681.
Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, et al
. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990;8:813-9.
Nguyen S, Leblanc T, Fenaux P, Witz F, Blaise D, Pigneux A, et al
. A white blood cell index as the main prognostic factor in t(8;21) acute myeloid leukemia (AML): A survey of 161 cases from the French AML Intergroup. Blood 2002;99:3517-23.
Schlenk RF, Benner A, Krauter J, Büchner T, Sauerland C, Ehninger G, et al
. Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: A survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol 2004;22:3741-50.
Delaunay J, Vey N, Leblanc T, et al
. Prognosis of inv(16)/t(16;16) acute myeloid leukemia(AML): A survey of 110 cases from the French AML Intergroup. Blood 2003;102:462-9
Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, et al
. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009;114:144-7.
Gelsi-Boyer V, Trouplin V, Adélaïde J, Bonansea J, Cervera N, Carbuccia N, et al
. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol 2009;145:788-800.
Abdel-Wahab O, Manshouri T, Patel J, Harris K, Yao J, Hedvat C, et al
. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res 2010;70:447-52.
Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al
. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009;361:1058-66.
Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrózek K, Margeson D, et al
. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo
cytogenetically normal acute myeloid leukemia: A Cancer and Leukemia Group B study. J Clin Oncol 2010;28:2348-55.
Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al
. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010;17:225-34.
Yamashita Y, Yuan J, Suetake I, Suzuki H, Ishikawa Y, Choi YL, et al
. Array-based genomic resequencing of human leukemia. Oncogene 2010;29:3723-31.
Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al
. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010;363:2424-33.
Yan XJ, Xu J, Gu ZH, Pan CM, Lu G, Shen Y, et al
. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 2011;43:309-15.
Van Vlierberghe P, Patel J, Abdel-Wahab O, Lobry C, Hedvat CV, Balbin M, et al
. PHF6 mutations in adult acute myeloid leukemia. Leukemia 2011;25:130-4.
Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al
. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012;481:506-10.
Lee JH, Joo YD, Kim H, Bae SH, Kim MK, Zang DY, et al
.; Cooperative Study Group A for Hematology. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood 2011;118:3832-41.
Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, et al
.; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009;361:1235-48.
Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al
. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012;366:1079-89.
[Table 1], [Table 2]