A Programme of Treatment Development for Older Patients With Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome

Trial Information

A Programme of Treatment Development for Older Patients With Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome

OBJECTIVES:

Primary (patients considered fit for intensive treatment)

- Compare the efficacy and toxicity of daunorubicin hydrochloride and cytarabine (DA) vs
daunorubicin hydrochloride and clofarabine (DClo) as induction therapy in older
patients with acute myeloid leukemia or high-risk myelodysplastic syndromes.

- Assess the value of gemtuzumab ozogamicin when given in combination with DA or DClo
during course 1 of induction therapy.

- Compare a total of two vs three courses of treatment in patients who achieve at least
partial remission (< 15% blasts) after course 1 of induction therapy.

- Compare the use of demethylation maintenance therapy comprising azacitidine vs no
maintenance therapy in these patients.

- Assess the value of reduced-intensity allogeneic stem cell transplantation as
consolidation in patients with matched donors.

Primary (patients considered unfit for intensive treatment)

- Compare the efficacy and toxicity of low-dose cytarabine with vs without gemtuzumab
ozogamicin in these patients.

- Compare the efficacy and toxicity of low-dose cytarabine with vs without arsenic
trioxide in these patients.

- Compare the efficacy and toxicity of low-dose cytarabine vs low-dose clofarabine in
these patients.

Secondary

- Evaluate the relevance of the presence of a cytogenetic abnormality in the bone marrow
of patients in morphological remission.

- Correlate molecular detection of FLT3 and RAS mutation, genetic signature, and
resistance protein status with response to treatment.

- Evaluate methods of minimal residual disease monitoring.

- Correlate gene methylation status with treatment with maintenance azacitidine.

OUTLINE: This is a randomized, controlled, factorial design, prospective, multicenter study.
Patients are stratified according to age (< 60 years vs 60-64 years vs 65-69 years vs 70-74
years vs ≥ 75 years), performance status, WBC count (0-9.9,000/mm³ vs 10-49.9,000/mm³ vs
50-99.9,000/mm³ vs ≥ 100,000/mm³), and type of disease (de novo acute myeloid leukemia [AML]
vs secondary AML vs high-risk myelodysplastic syndromes). Patients receive treatment
according to disease status (fit for intensive treatment vs unfit for intensive treatment).

- Intensive treatment (for patients considered fit for intensive treatment):

- Induction therapy: Patients are randomized to 1 of 4 treatment arms.

- Arm I: For course 1, patients receive daunorubicin hydrochloride (DH) IV over
1 hour on days 1, 3, and 5 and cytarabine IV twice daily on days 1-10. For
course 2, patients receive DH as in course 1 and cytarabine IV twice daily on
days 1-8. Courses are 4 weeks in duration.

- Arm II: Patients receive DH IV over 1 hour on days 1, 3, and 5 and
clofarabine IV over 1 hour on days 1-5. Treatment repeats every 4 weeks for 2
courses.

- Arm III: For course 1, patients receive DH IV over 1 hour on days 1, 3, and
5, cytarabine IV twice daily on days 1-10, and gemtuzumab ozogamicin (GO) IV
over 2 hours on day 1. For course 2, patients receive DH as in course 1 and
cytarabine IV twice daily on days 1-8. Courses are 4 weeks in duration.

- Arm IV: For course 1, patients receive DH and clofarabine as in arm II and GO
as in arm III. For course 2, patients receive DH and clofarabine as in arm
II. Courses are 4 weeks in duration.

Patients who fail to achieve partial remission (PR) or complete remission (CR) after course
1 but achieve CR after course 2 receive a third course of chemotherapy comprising DH IV over
1 hour on days 1 and 3 and cytarabine IV twice daily on day 1-5. Patients then proceed to
randomization for maintenance therapy.

Patients who achieve PR or CR after course 1 and are in CR after course 2 are randomized to
receive or not receive a third course of chemotherapy (as above). Patients then proceed to
randomization for maintenance therapy.

Patients who have an HLA-matched donor may proceed to nonintensive allogeneic stem cell
transplantation (ASCT).

- Nonintensive ASCT: Patients receive a nonintensive allograft comprising 1 of 2
mini-allograft protocols.

- Protocol 1: Patients receive fludarabine on days -9 to -5, busulfan on days -3 and
-2, and alemtuzumab on days -5 to -1. Patients undergo ASCT on day 0.

- Protocol 2: Patients receive fludarabine on days -7 to -3, melphalan on day -2,
and alemtuzumab on days -8 to -4. Patients undergo ASCT on day 0.

- Maintenance Therapy: Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive azacitidine subcutaneously (SC) once daily on days 1-5.
Treatment repeats every 6 weeks for 9 courses in the absence of disease
progression or unacceptable toxicity.

- Arm II: Patients do not receive maintenance therapy.

- Nonintensive treatment (for patients considered unfit for intensive
treatment): Patients are randomized to 1 of 4 treatment arms.

- Arm I: Patients receive low-dose cytarabine (LDC) SC twice daily on days 1-10.

- Arm II: Patients receive LDC as in arm I and GO IV over 2 hours on day 1.

- Arm III: Patients receive low-dose clofarabine IV over 1 hour once daily on days 1-5.

- Arm IV: Patients receive LDC as in arm I and arsenic trioxide IV over 1-2 hours on days
1-5, 9, and 11.

Treatment in all arms repeats every 4-6 weeks for 4 courses in the absence of disease
progression or unacceptable toxicity.

Bone marrow is collected at diagnosis and examined for characterization of FLT3 and RAS
mutations by immunophenotyping, gene expression by DNA microarray, and cytogenetic analysis.
Blood samples are collected at baseline and after 18, 36, and 54 weeks of treatment for
assessment of gene methylation status.

After completion of study therapy, patients are followed at 6 and 12 months and then
annually thereafter.

PROJECTED ACCRUAL: A total of 2,000 patients will be accrued for this study.