1. BACKGROUND AND RATIONALE 1.1. CLINICAL CHARACTERISTICS OF CBF AML Acute myeloid leukemia
      (AML) is a disease entity consisting of heterogeneous groups with different clinical features
      and prognosis. Cytogenetic status of patients with AML is the single most important factor to
      expect the survival and the treatment responses.

      Core binding factor (CBF) AML is characterized by the presence of cytogenetic abnormalities,
      i.e., the balanced translocation between chromosome 8 and 21 [t(8;21)(q22;q22)] and the
      pericentric inversion of chromosome 16 [inv(16)(p13q22)] or its less frequent variant, the
      balanced translocation t(16;16)(p13;q22). Among adults with de novo AML, t(8;21) and inv(16)
      are found in 7% and 8% of patients, respectively1. All the subtypes of CBF AML share the same
      chimeric fusion genes that are formed by the disruption of genes encoding different subunits
      of the core binding factor, a heterodimeric transcription factor complex.

      CBF AML has been accepted as a disease entity of favorable prognosis with a high complete
      remission rate (up to 90%) with conventional induction chemotherapy followed by an intensive
      consolidation treatment of 3 or 4 cycles of high-dose cytarabine(HDAC). The overall survival
      of patients in this group rise up to 60 - 70 %, and this encouraging result has supported the
      opinion that HDAC was a more preferable postremission therapy instead of autologous
      hematopoietic cell transplantation (HCT) or allogeneic HCT.

      1.2. STRATEGY TO REDUCE RELAPSE IN CBF AML It has been thought that patients with CBF AML in
      first complete remission (CR1) would benefit most from high-dose consolidation chemotherapy
      and the risk of HCT outweigh the benefit in this group. However, the cumulative incidence of
      relapse (CIR) has been reported to be up to 54% and 50-60% of patients are cured using
      contemporary treatment. The survival outcome is unsatisfactory, especially in elderly
      patients. Prebet et al reported that the 5-year probabilities of overall survival (OS) and
      leukemia-free survival (LFS) were 31% and 27%, respectively with intensive consolidation or
      low-dose maintenance chemotherapy among patients with CBF AML who were age 60 years or older.
      To improve the treatment outcome in this group, alternative strategies of postremission
      therapy with more efficiency and more tolerability are warranted, especially for patients who
      are prone to relapse. A number of studies about the stratified intensification of
      postremission therapy according to the risk of relapse and the appropriate prognostic index
      for identifying high risk patients have been reported, and some of them are currently under
      investigation.

      1.3. DIFFERENCES BETWEEN AML WITH INV(16) AND WITH T(8;21) Recent studies have reported that
      these two groups seem to be distinct clinical entities and should be stratified and reported
      separately. Patients with t(8;21) had shorter OS (hazard ratio [HR] =1.5, p=0.045) and
      survival after first relapse (HR=1.7, p=0.009) than patients with inv(16). A similar
      difference was found among patients who had undergone HCT; the 3-year OS of patients with
      t(8;21) and inv(16) was 50% and 72%, respectively(p=0.002). Based on these results, a
      discriminative postremission strategy could be applied to patients with CBF AML - patients
      with t(8;21) should be managed differently from those with inv(16) as to the application of
      HCT and a prospective trial can be warranted to clarify the significance of HCT over
      chemotherapy.

      1.4. RISK STRATIFICATION IN AML WITH INV(16) Although AML with inv(16) has a relatively good
      prognosis, a substantial number of these patients (i.e. 40-50%) finally relapse. In this
      group, timely identification and therapeutic stratification of patients who deemed at high
      risk for relapse could ultimately result in an improvement of clinical outcomes. The minimal
      residual disease (MRD) monitoring with real-time quantitative polymerase chain reaction
      (RQ-PCR) assays for CBFβ/MYH11 fusion transcript has been regarded as a useful surrogate
      marker for identifying a patient with resistant disease and for predicting relapse early
      during remission. Lane et al reported that a rise of the same or more than 1 log rise of
      transcript level relative to the level from a remission bone marrow sample at any time of
      post-induction follow up correlated with inferior LFS and morphologic relapse (HR 8.6).
      Bounamici et al suggested that patients whose transcript ratios of bone marrow samples taken
      during remission were greater than 0.25% finally relapse, and ratio below 0.12% might
      indicate that patients is in a curable state.

      Two conclusions can be deduced from the results above; first, a considerable portion of
      patients among those with CBF AML finally relapse. Second, post-induction MRD monitoring
      might be helpful in discriminating patients who are vulnerable to relapse and may have
      benefit with more intensified consolidation therapy.

      1.5. RISK STRATIFICATION IN AML WITH T(8;21) AML with t(8;21) has been accepted as a disease
      of good prognosis and categorized to favorable cytogenetic risk group along with AML with
      inv(16). According to recent studies, however, outcomes of AML patients with t(8;21) were
      disappointing in contrary to those with previous ones. The biologic and prognostic
      heterogeneity have been recently described for this subgroup (including other subtypes of CBF
      AML) and a number of promising biologic markers have been suggested.

      MRD monitoring with RQ-PCR or flow cytometry is also thought as a useful method for the
      stratification of patients with t(8;21), as well as for those with inv(16). C-kit mutation
      has been generally accepted as a discriminating marker of CBF AML which increase the relapse
      risk. A difference in race has been considered as an important predictor for t(8;21) AML, in
      that nonwhites failed induction more often and had shorter OS than white. Other biomarkers
      which has been being considered are leukocyte count or white blood cell, CD56 positivity,
      loss of sex chromosome and secondary cytogenetic abnormalities6, submicroscopic deletion
      during chromosome rearrangement, loss of MRP gene during translocation / inversion and
      presence of RAS/FLT3 mutation. Gene-expression profile is suggested as a relevant way of
      molecular characterization to discriminate substantial biologic and clinical heterogeneity
      within CBF AML.

      1.6. COMPARISON OF POSTREMISSION THERAPY FOR CBF AML The optimal postremission therapy of CBF
      AML remains to be determined. Despite being considered as patients in more favorable risk
      group in AML, only approximately half of the patients are cured with current strategy,
      significant portion of patients finally relapse and the overall survival is unsatisfactory.
      Heterogeneity of the treatment outcome in this group also suggests that a tailored approach
      might be preferred to a unique predefined strategy to treat. Current state of CBF AML
      indicates the need for improved therapeutic approaches, including more intensive
      consolidation to obtain improved LFS.

      There were a few prospective studies that support the role of HCT. A prospective trial on the
      impact of cytogenetics and the kind of consolidation therapy performed by Visani et al showed
      that patients in the favorable group had significantly longer disease-free survival(DFS) when
      treated with an intensive induction and allogeneic HCT as an intensive consolidation therapy.
      According to the result of MRC AML 10 randomized controlled trial comparing the addition of
      autologous HCT with intensive chemotherapy alone for AML in CR1, addition of autologous HCT
      to four course of intensive chemotherapy reduced the risk of relapse, increased disease-free
      survival significantly, and improved the overall survival, although there were more death in
      remission in the autologous HCT group. However, a number of studies support the classic
      concept that CBF AML in CR1 would benefit most from HDAC and the risk of HCT outweigh the
      benefit. Delaunay et al reported that outcome of patients with inv(16) in CR1 was similar
      among patients allocated to receive allogeneic HCT vs HDAC8. According to the meta-analysis
      performed on 392 adults with CBF AML in prospective German AML treatment trial, type of
      postremission therapy revealed no difference between intensive chemotherapy and autologous
      HCT in the t(8;21) group and between chemotherapy, autologous HCT, and allogeneic HCT in the
      inv(16) group. Recent results suggest the possibility of improving overall survival with HCT.
      Subgroup analysis of EORTC-LG/GIMEMA AML-10 trial in which patients younger than 46 years
      were assigned to allogeneic HCT or autologous HCT according to the availability of
      HLA-identical sibling donor, DFS rate were similar in patients with good risk cytogenetics.
      Kuwatsuka et al reported a retrospective analysis on the results of HCT performed on CBF AML.
      OS was not different between patients in CR1 who received allogeneic HCT and those who
      received autologous HCT for both t(8;21) AML (84% vs 77%; p=0.49) and inv(16) AML (74% vs
      59%, p=0.86).

      1.7. OPTIMAL POSTREMISSION THERAPY FOR CBF AML In summary, HDAC chemotherapy has been
      recommended as a relevant postremission therapy for patients with CBF AML in CR1 on the basis
      that risk of HCT outweigh the clinical benefit of reducing the incidence of relapse and
      prolonging LFS. With the advances in hematopoietic cell transplantation technique and
      biomarkers for risk stratification, HCT is now considered for a promising method to improve
      the overall outcome of patients with CBF AML. Until now, previous results support the
      introduction of autologous HCT rather than allogeneic HCT for intensified postremission
      therapy in CBF AML in that the benefit of HCT was not yet proven and the risk of allogeneic
      HCT might outweigh the benefit in this group. We hereby intend to evaluate the efficacy of
      autologous HCT in patients with CBF AML in CR1.