Trial Information

A Prospective Randomized Comparison of Idarubicin and High-dose Daunorubicin in Combination With Cytarabine in the Induction Chemotherapy for Acute Myeloid Leukemia

1. INDUCTION CHEMOTHERAPY

- For patients randomized to receive Idarubicin (Arm I, AI regimen) will be given
Cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 7 days
(D 1-7) along with Idarubicin 12 mg/m2/day iv daily for 3 days (D 1-3).

- For patients randomized to receive Daunorubicin (Arm II, AD regimen) will be given
Cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 7 days
(D 1-7) along with Daunorubicin 90 mg/m2/day iv daily for 3 days (D 1-3).

2. INTERIM BONE MARROW EXAMINATION

- Bone marrow aspiration and biopsy will be done between 14 to 21 days after start
of induction chemotherapy.

- If the bone marrow is hypoplastic and contains no more than 5% blast cells,
further chemotherapy will be deferred and the marrow examination will be repeated
at the time of neutrophils over 1,000/mcL and platelets over 100,000/mcL in the
peripheral blood for the evaluation of complete remission.

- If more than 5% blast cells persist at interim or later repeated bone marrow
examination, a course of re-induction chemotherapy will be given.

3. RE-INDUCTION CHEMOTHERAPY

-Reinduction chemotherapy

- Arm I (AI regimen) : Cytarabine 200 mg/m2/day by continuous iv infusion over 24
hours daily for 5 days (D 1-5) plus idarubicin 8 mg/m2/day iv daily for 2 days (D
1-2)

- Arm II (AD regimen) : Cytarabine 200 mg/m2/day by continuous iv infusion over 24
hours daily for 5 days (D 1-5) plus Daunorubicin 45 mg/m2/day iv daily for 2 days
(D 1-2) .Reinduction chemotherapy should be delayed if there is a significant
infection or other co-morbid medical condition.

- Patients who do not have a complete remission after a second course of induction
chemotherapy will be removed from the study

4. POSTREMISSION CHEMOTHERAPY .The same postremission therapy will be given to the
patients in both arms. .For patients with good- or intermediate-risk cytogenetic
features or unknown cytogenetics (see appendix II), 4 courses of high-dose cytarabine
will be given as post-remission therapy. Cytarabine 3 g/m2 will be administered in a
3-hour iv infusion every 12 hours on days 1, 3, and 5 (a total of six doses per
course).

.For patients with high-risk cytogenetic features (see appendix II), 4 courses of
intermediate-dose Cytarabine plus Etoposide will be given as post-remission therapy.
Cytarabine 1 g/m2 will be given in a 1-hour iv infusion on days 1 to 6 (a total of six
doses per course) and Etoposide 150 mg/m2/day will be administered in a 5-hour iv
infusion on days 1 to 3 (a total of three doses per course).

.Sequential courses of postremission therapy will be given no sooner than every 28 days
or 1 week after adequate marrow recovery.

.Postremission chemotherapy should be delayed if there is a significant infection or
other co-morbid medical condition.

.One or two doses of Cytarabine can be omitted according to the attending physician's
decision for the followings: .Marrow recovery requires more than 28 days.

- A confluent maculopapular eruption or drug-induced desquamation

- Photophobia or conjunctivitis unrelieved within 24 hours by ophthalmic steroid
drops

- More than 4 episodes of watery diarrhea per day

- A fourfold increase in a previously normal serum aminotransferase or alkaline
phosphatase level or a total bilirubin level exceeding 3.0 mg/dL .Treatment with
high-dose cytarabine will be discontinued in patients with severe cerebellar
ataxia, confusion, or other central nervous system signs thought to be unrelated
to antiemetic medication.

5. EVALUATION DURING TREATMENT .During induction and consolidation chemotherapy: CBC with
differentials (daily), chemical battery with electrolyte (twice a week), coagulation
battery (once a week), chest x-ray (once a week).

.Bone marrow examination will be repeated on day 15 of induction chemotherapy (for the
evaluation of hypocellular marrow) and at the time of ANC ≥ 1,000/μl and platelets ≥
100,000/μl in the peripheral blood (for the evaluation of complete remission).
Chromosomal analysis will be repeated at the time of the evaluation of complete
remission.

6. POST-TREATMENT FOLLOW-UP

.After the completion of postremission treatment (i.e. following consolidation
chemotherapy or HCT): CBC with differentials (monthly for the first 12 months, then
every 2-3 months for the next 4 years), other studies such as MRD monitoring (as
indicated)

7. TREATMENT EVALUATION *FFICACY EVALUATION

- Complete remission (CR): Bone marrow blasts < 5%; absence of blasts with Auer
rods; absence of extramedullary disease; absolute neutrophil count > 1,000/mcL;
platelet count > 100,000/mcL; independence of red cell transfusion (Döhner H et
al, 2010).

- All criteria need to be fulfilled; marrow evaluation should be based on a count of
200 nucleated cells in an aspirate with spicules; if ambiguous, consider repeat
exam after 5 to 7 days; flow cytometric evaluation may help to distinguish between
persistent leukemia and regenerating normal marrow; a marrow biopsy should be
performed in cases of dry tap, or if no spicules are obtained; no minimum duration
of response required.

- CR with incomplete recovery (CRi): All CR criteria except for residual neutropenia
(< 1,000/mcL) or thrombocytopenia (< 100,000/mcL).

- Cause of treatment failure

- Resistant disease (RD): Failure to achieve CR or CRi; only includes patients
surviving ≥ 7 days following completion of initial treatment, with evidence of
persistent leukemia by blood and/or bone marrow examination.

- Death in aplasia: Deaths occurring ≥ 7 days following completion of initial
treatment while cytopenic; with an aplastic or hypoplastic bone marrow obtained
within 7 days of death, without evidence of persistent leukemia.

- Death from indeterminate cause: Deaths occurring before completion of therapy, or
< 7 days following its completion; or deaths occurring ≥ 7 days following
completion of initial therapy with no blasts in the blood, but no bone marrow
examination available.

- Relapse: Bone marrow blasts ≥ 5%; or reappearance of blasts in the blood; or
development of extramedullary disease.

- In cases with low blast percentages (5-10%), a repeat marrow should be performed
to confirm relapse. Appearance of new dysplastic changes should be closely
monitored for emerging relapse. In a patient who has been recently treated,
dysplasia or a transient increase in blasts may reflect a chemotherapy effect and
recovery of hematopoiesis. Cytogenetics should be tested to distinguish true
relapse from therapy-related MDS/AML.