Primary study objective is the evaluation of efficacy of autologous hematopoietic cell
transplantation (HCT) with core-binding factor (CBF) positive acute myeloid leukemia (AML) in
the first CR (CR1) in terms of relapse incidence (cumulative incidence of relapse, CIR) and
disease-free survival (DFS).
Secondary study objectives are the engraftment rate / time to engraftment,
transplantation-related mortality (TRM) rate, event-free survival (EFS) rate, and Overall
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
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
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
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.
- Patients with CBF positive AML in CR1. CBF AML includes t(8;21)(q22;q22)
[AML1(RUNX1)/ETO(CBFα2T1)], inv(16)(q13q22) (CBFβ/MYH11), t(16;16)(p13;q22)
(CBFβ/MYH11) Using RT-PCR, FISH, or standard karyotype analysis technique.
- Patients who plan to receive the second cycle of HDAC consolidation chemotherapy.
- 15 years old or older and 65 years or younger
- Adequate performance status (Karnofsky score of 70 or more).
- Adequate hepatic and renal function (AST, ALT, and bilirubin < 3.0 x upper normal
limit, and creatinine < 2.0 mg/dL).
- Adequate cardiac function (left ventricular ejection fraction over 40% on heart scan
- Signed and dated informed consent must be obtained from patient.
- Presence of significant active infection
- Presence of uncontrolled bleeding
- Any coexisting major illness or organ failure
- Patients with psychiatric disorder or mental deficiency severe as to make compliance
with the treatment unlike, and making informed consent impossible
- Nursing women, pregnant women, women of childbearing potential who do not want
- Patients with a diagnosis of prior malignancy unless disease-free for at least 5 years
following therapy with curative intent (except curatively treated nonmelanoma skin
cancer, in situ carcinoma, or cervical intraepithelial neoplasia)