Phase 2 Study of Autologous Hematopoietic Cell Transplantation for Core-binding Factor Positive Acute Myeloid Leukemia in the First Complete Remission

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.