Muller Journal of Medical Sciences and Research

: 2015  |  Volume : 6  |  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

Correspondence Address:
Farooq Ahmad Ganie
Department of Cardiovascular and Thoracic Surgery, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Soura, Srinagar, Jammu and Kashmir


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.

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;6:35-39

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 2023 Feb 5 ];6:35-39
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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. [1] 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. [2],[3] 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. [4] 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. [5],[6],[7],[8],[9],[10] 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. [11] In inv(16) AMLs, CBFB located at 16q22 is fused to the MYH11 gene located at 16p13. [12] Both translocations are thought to lead to leukemia by creating fusion products that are dominant negative inhibitors of normal myeloid differentiation. [13],[14] 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. [15],[16] The incidence of CBF-AML decreases with age, and is it represents less than 5% in those of age 60 years and above. [17],[18] The elderly patients with CBF-AML have higher CR rates and longer survival times [17],[19] compared with patients who have other types of AML. However, the outcome seems inferior to that of younger patients. [20],[21],[22],[23] Appelbaum et al., [21] 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 [24] and flow cytometric analysis of bone marrow samples simultaneously. All karyotypes were interpreted according to the International System for Human Cytogenetic Nomenclature. [25] All our patients had the translocation 8;21.

All these patients were enrolled for standard chemotherapy regimen [26] 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. [27] 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.


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.{Table 1}

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.

Subsequent Follow-up

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.{Table 2}


Previous studies have evaluated the prognostic and clinical characteristics of patients with t(8;21) and inv(16) AML, [28],[29],[30] 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, [31],[32] ASXL1, [33],[34] IDH1[35] and IDH2, [36],[37] DNMT3A,[38],[39] and PHF6. [40] 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. [41] 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. [42] A similar study in patients older than 60 years [43] 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. [44] 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.


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.


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