Tretinoin and Arsenic Trioxide With or Without Idarubicin in Treating Patients With Acute Promyelocytic Leukemia

Memorial Sloan Kettering Cancer Center (MSK)

Status and phase

Terminated

Phase 2

Conditions

Leukemia

Treatments

Drug: tretinoin

Drug: arsenic trioxide

Drug: idarubicin

Study type

Interventional

Funder types

Other

Industry

NIH

Identifiers

NCT00528450

P30CA008748 (U.S. NIH Grant/Contract)

CEPHALONO-MSKCC-07108

MSKCC-07108

07-108

Details and patient eligibility

About

RATIONALE: Tretinoin may help cancer cells become more like normal cells, and to grow and spread more slowly. Drugs used in chemotherapy, such as arsenic trioxide and idarubicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving tretinoin together with arsenic trioxide with or without idarubicin may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving tretinoin together with arsenic trioxide with or without idarubicin works in treating patients with acute promyelocytic leukemia.

Full description

OBJECTIVES:

Primary

To determine the rate of molecular remission after induction therapy comprising tretinoin (ATRA) and arsenic trioxide (ATO) (along with idarubicin in patients with leukocytosis) in patients with acute promyelocytic leukemia (APL).

Secondary

To determine the rate of clinical complete remission and the time to remission after induction therapy.
To determine the proportion of patients in molecular remission after each course of postremission therapy and to use these findings to direct the number of consolidation courses with ATRA and idarubicin that are administered.
To determine the disease-free survival and overall survival of patients treated with this regimen.
To determine the toxicity of this treatment regimen, including the number and length of hospitalizations, the incidence of secondary myelodysplastic syndromes or acute myeloid leukemia, and the effects of treatment on LVEF.
To characterize the differentiation of APL cells during treatment with combined ATRA and ATO using serial immunophenotyping studies of peripheral blood and bone marrow.
To compare the results of quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assays performed on bone marrow and peripheral blood.

OUTLINE:

Induction therapy: Patients receive tretinoin orally twice daily and arsenic trioxide IV over 1-4 hours once daily until a marrow remission is documented or for 60 days, whichever comes first. Patients with leukocytosis (WBC > 10,000/μL) also receive idarubicin IV over 10-15 minutes beginning on day 2 and continuing every other day for 4 doses. Patients who achieve a clinical complete remission (CR) proceed to consolidation therapy. If a marrow remission is not achieved after 60 days, the patient is removed from the study.
Consolidation therapy:
- Consolidation courses 1, 2, and 3: Beginning 3-6 weeks after documentation of clinical CR, patients receive consolidation therapy comprising tretinoin orally twice daily for 15 days and arsenic trioxide IV over 1-4 hours once daily 5 days a week for 5 weeks. Consolidation therapy repeats every 3-6 weeks for 3 courses.

Patients who have a negative PML-RARα transcript by reverse transcriptase-polymerase chain reaction (RT-PCR) assay after consolidation course 2 proceed to maintenance therapy after receiving consolidation course 3. Patients who have a negative PML-RARα transcript by RT-PCR assay after consolidation course 3, proceed to consolidation course 4 followed by maintenance therapy. Patients who have a positive PML-RARα transcript by RT-PCR assay after consolidation courses 2 and 3 proceed to consolidation courses 4 and 5.

Consolidation course 4: Beginning 3-6 weeks after completion of consolidation course 3, patients receive tretinoin orally twice daily for 15 days and idarubicin IV over 10-15 minutes once daily for 4 days.
Consolidation course 5: Beginning 3-6 weeks after completion of consolidation course 4, patients receive tretinoin orally twice daily for 15 days and idarubicin IV over 10-15 minutes once daily for 3 days.

Patients who remain positive for the PML-RARα transcript after 5 courses of consolidation therapy are removed from the study. Patients who have a negative PML-RARα transcript after 5 courses of consolidation therapy proceed to maintenance therapy.

Maintenance therapy: Beginning approximately 3 months after completion of the final consolidation course, patients receive tretinoin orally twice daily for 15 days. Treatment repeats every 3 months for up to 2 years.

Disease status will be monitored with serial analyses of bone marrow and peripheral blood samples using RT-PCR for PML-RARα mRNA. Patients will be followed until relapse, death, loss to follow-up, or removal from study.

Enrollment

1 patient

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Morphologic diagnosis of acute promyelocytic leukemia (APL), confirmed by one of the following:
- Demonstration of t(15;17) using conventional cytogenetics or fluorescence in situ hybridization (FISH)
- Positive PML-RARα transcript by reverse transcriptase-polymerase chain reaction (RT-PCR) assay
Patients with CNS involvement by APL are eligible

PATIENT CHARACTERISTICS:

Karnofsky performance status 60-100%
Creatinine ≤ 2.0 mg/dL or creatinine clearance > 60 mL/min
Bilirubin < 2.0 mg/dL (unless attributed to Gilbert disease)
Alkaline phosphatase ≤ 2.5 times the upper limit of normal (ULN)
AST and ALT ≤ 2.5 ULN
LVEF ≥ 50% on echocardiogram or MUGA scan
QTc ≤ 500 msec on baseline ECG
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for ≥ 4 months after the completion of study treatment
No active serious infections not controlled by antibiotics
No other concurrent active malignancy requiring immediate therapy
No clinically significant cardiac disease (New York Heart Association class III or IV heart disease), including chronic arrhythmias
No pulmonary disease
No other serious or life-threatening condition deemed unacceptable by the principal investigator