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

Condition(s) targeted: Leukemia

Intervention: arsenic trioxide (Drug); idarubicin (Drug); tretinoin (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: Memorial Sloan Kettering Cancer Center

Official(s) and/or principal investigator(s):
Joseph G. Jurcic, MD, Principal Investigator, Affiliation: Memorial Sloan Kettering Cancer Center
Peter Maslak, MD, Principal Investigator, Affiliation: Memorial Sloan Kettering Cancer Center

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.

Official title: Phase II Study of Combined All-Trans Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy

Study design: Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Molecular remission rate

Secondary outcome:

Clinical complete remission rate

Proportion of patients who negative for disease by RT-PCR at study entry, after induction therapy, after each course of tretinoin (ATRA) and arsenic trioxide, and after each course of ATRA and idarubicin

Median time to clinical and molecular remissions

Disease-free survival

Overall survival

Toxicity as measured by NCI CTCAE version 3.0

Number of hospitalizations and number of hospital days

Incidence of secondary myelodysplastic syndromes/acute myeloid leukemia

Comparison of the results of quantitative real-time RT-PCR assays for the PML-RARα transcript on bone marrow and peripheral blood

Correlation of immunophenotyping of peripheral blood during induction therapy with expression of surface antigens, including CD33 and CD11b, over time

Detailed 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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 PRIOR CONCURRENT THERAPY:

- No prior treatment for APL

Memorial Sloan-Kettering Cancer Center, New York, New York 10021, United States

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: September 2007
Last updated: March 15, 2013