Trial Information

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.

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.