Clinical Trial: Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: Phase II Study of Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy

Brief Summary:

The purpose of this study is to find what effects, good and/or bad, treatment with two drugs has on leukemia. The first medicine is tretinoin (also called all-trans retinoic acid, ATRA, or Vesanoid). It is an approved medicine that causes the leukemia cells in APL to mature. It is related to vitamin A. The second is arsenic trioxide (Trisenox). It is an approved medicine for APL that comes back after earlier treatment.

APL is most often treated with tretinoin and standard chemotherapy drugs. These chemotherapy drugs can cause infection and bleeding. They can also damage the heart and normal bone marrow cells. This can lead to a second leukemia years later.

In this study, the investigators are using tretinoin and arsenic trioxide together. Both drugs work to treat APL. They have been used together in only a limited number of people. The investigators want to use these drugs together to reduce the amount of standard chemotherapy and decrease side effects. The patient will receive standard chemotherapy with a drug called idarubicin only if they have a higher chance of the leukemia coming back or a higher risk of side effects.

Detailed Summary:

Induction will consist of tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) in two divided doses (25 mg/m2 in patients <20 years of age) for 35 days and ATO 0.15 mg/kg IV daily for 35 doses given 5-7 days per week. The drugs will then be discontinued, and the patient will be followed until a clinical complete remission is achieved. Idarubicin 12 mg/m2 IV for 4 doses will be added during induction on day 2 if the presenting WBC is >10,000/μl, or if the WBC increases to 5,000/μl on day 5, 10,000/μl on day 10, or 15,000/μl on day 15, because of the increased risk of the APL differentiation syndrome and relapse in these patients. Dexamethasone 10 mg twice daily with be given on days 1-14 of induction as prophylaxis for the APL differentiation syndrome. All patients will then receive four courses of consolidation with tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) (25 mg/m2 in patients <20 years of age) for 15 days and ATO 0.15 mg/kg IV for 25 doses.

Patients with high-risk disease or who received Idarubicin during Induction may receive intrathecal cytarabine as CNS prophylaxis given by the treating physician during consolidation, at the discretion of the site PI. High-risk patients will also receive maintenance therapy with additional courses of tretinoin and ATO every 3 months for 2 years. Each maintenance course will consist of tretinoin 45 mg/m2 po daily (25 mg/m2 in patients <20 years of age) for 15 days and ATO 0.15 mg/kg IV for 10 doses. Disease status will be monitored with serial analyses of 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.

Induction therapy can be given as an inpatient or outpatient. Consolidation and maintenance treatments will be given as an o
Sponsor: Memorial Sloan Kettering Cancer Center

Current Primary Outcome: To determine the rate of molecular remission [ Time Frame: 4 years ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• To determine the rate of clinical complete remission (CR) and the time to remission [ Time Frame: 4 years ]
  after induction with tretinoin and ATO (with idarubicin in patients with high-risk disease or who develop leukocytosis).
• To determine the proportion of patients in molecular remission [ Time Frame: 4 years ]
  after each course of postremission therapy.
• To determine the disease-free and event-free survival of patients [ Time Frame: 4 years ]
  treated with this program.
• To determine the toxicity of this treatment program [ Time Frame: 4 years ]
  including the early death rate (within 30 days), the incidence of APL differentiation syndrome, the number and length of hospitalizations, the incidence of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), and the effects of treatment on left ventricular ejection fraction (LVEF) Frequencies of toxicities based on the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 will be tabulated.
• To characterize the differentiation of APL cells during treatment [ Time Frame: 4 years ]
  with combined tretinoin and ATO using serial immunophenotyping studies of peripheral blood
• Explore the in vivo induction of telomerase-dependent cell death [ Time Frame: 4 years ]
  by ATRA (Tretinoin) and ATO (Arsenic Trioxide). Bone marrow samples will be analyzed at baseline and at the time of clinical CR for telomerase activity, telomere length and TERT expression

Original Secondary Outcome:

• To determine the rate of clinical complete remission (CR) and the time to remission [ Time Frame: 4 years ]
  after induction with tretinoin and ATO (with idarubicin in patients with high-risk disease or who develop leukocytosis).
• To determine the proportion of patients in molecular remission [ Time Frame: 4 years ]
  after each course of postremission therapy.
• To determine the disease-free, event-free, and overall survival of patients [ Time Frame: 4 years ]
  treated with this program.
• To determine the toxicity of this treatment program [ Time Frame: 4 years ]
  including the early death rate (within 30 days), the incidence of APL differentiation syndrome, the number and length of hospitalizations, the incidence of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), and the effects of treatment on left ventricular ejection fraction (LVEF) Frequencies of toxicities based on the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 will be tabulated.
• To characterize the differentiation of APL cells during treatment [ Time Frame: 4 years ]
  with combined tretinoin and ATO using serial immunophenotyping studies of peripheral blood
• Explore the in vivo induction of telomerase-dependent cell death [ Time Frame: 4 years ]
  by ATRA (Tretinoin) and ATO (Arsenic Trioxide). Bone marrow samples will be analyzed at baseline and at the time of clinical CR for telomerase activity, telomere length and TERT expression

Dates:
Date Received: July 27, 2011
Date Started: July 2011
Date Completion: July 2018
Last Updated: December 21, 2016
Last Verified: December 2016