Modified Hyper-CVAD (Cyclophosphamide, Vincristine, Adriamycin, and Dexamethasone) Program for Acute Lymphoblastic Leukemia

Condition(s) targeted: Leukemia; Acute Lymphoblastic Leukemia

Intervention: Rituximab (Drug); Cyclophosphamide (CTX) (Drug); Doxorubicin (Drug); Vincristine (Drug); Dexamethasone (Drug); Methotrexate (MTX) (Drug); Cytarabine (Drug); G-CSF (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: M.D. Anderson Cancer Center

Official(s) and/or principal investigator(s):
Susan O'Brien, M.D., Principal Investigator, Affiliation: M.D. Anderson Cancer Center

Overall contact:
Susan O'Brien, M.D., Phone: 713-792-7543, Email: sobrien@mdanderson.org

The goal of this clinical research study is to learn if intensive chemotherapy (with monoclonal antibody therapy in some patients) given for 8 courses over 5 to 6 months followed by monthly maintenance chemotherapy for 2 1/2 years can improve or cure acute lymphoblastic leukemia or lymphoblastic lymphoma.

Official title: Phase II Study of The Modified Hyper-CVAD Program for Acute Lymphoblastic Leukemia

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

Primary outcome: Overall Response Rate

Detailed description: The hyper-CVAD regimen is a combination of chemotherapy drugs including cyclophosphamide, vincristine, Adriamycin, and dexamethasone given together to for one "course" of treatment. This alternates with a course or combination of the chemotherapy drugs methotrexate and ara-C. Rituximab is a protein (monoclonal antibody) that attaches to the surface of the leukemia or lymphoma cells, which have a marker, called "CD20".

Before treatment starts, participants will have a complete physical exam, including blood (about 8 teaspoons) and urine tests. A chest X ray will be taken. CT scans may be taken if needed. A bone marrow sample will be taken through a large needle in the hipbone. Women able to have children must have a negative blood pregnancy test. An ECG (tracing of the heart) and a cardiac scan will be taken.

All participants will receive 2 kinds of chemotherapy courses for a total of 8 courses. Chemotherapy courses will be given through a large vein by a central venous catheter (a plastic tube usually placed under the collarbone).

During treatment, participants will have a physical exam and give blood samples (about 1 tablespoon each) at least twice a week. After two courses of chemotherapy, the tests done before treatment will be repeated to check for response. In patients with acute lymphoblastic leukemia or lymphoblastic lymphoma with marrow disease, a bone marrow sample will be repeated 2 and 3 weeks from the beginning of treatment to check the response.

Course 1 (odd courses) will start by giving rituximab by vein over 6 hours on Day 1 and Day 11 for patients whose leukemia expresses CD20. After a 6-hour rest period, participants will receive the cyclophosphamide as described below.

Participants will receive the drugs acetaminophen (Tylenol) and diphenhydramine hydrochloride (Benadryl) 30 60 minutes before each dose of rituximab. This will be done to lessen the risk of fever, chills, and allergic reactions. Usually, the first dose of rituximab requires about 6 hours to complete. If side effects do occur during the infusion, participants will be observed for an additional 2 hours after the rituximab is given.

Other participants who do not have the CD20 marker will start Course 1 with cyclophosphamide given by vein over 2 3 hours every 12 hours. This will be given for 6 doses over 3 days (Days 1,2, and 3). Adriamycin will be given by vein over 2 3 hours on Day 4. Vincristine will be given by vein over 15 to 30 minutes on Days 4 and 11. Dexamethasone (a steroid) will be given by mouth or by vein on Days 1 to 4 and 11 to 14.

Pegfilgrastim (a growth colony stimulating factor) will be given after each course of chemotherapy is finished. It is given to help with rapid recovery of the normal marrow. G- Pegfilgrastim will be injected under the skin within 72 hours of completion of each cycle of chemotherapy.

Treatment to the brain will be given inside the spinal fluid with methotrexate around day 2 and cytarabine (ara-C) about day 7 of the course. This is done to decrease the risk that the leukemia will develop there.

For patients aged 60 years or older, this first course of chemotherapy will be given in a protective isolation room to decrease the risk of infection(s).

During Course 2, participants whose leukemia expresses CD20 will receive rituximab by infusion over 4 hours on Days 1 (6 hours before the next drug, methotrexate) and 8. Other participants who do not have CD20 on the leukemia cells will start with methotrexate by infusion over 24 hours on the first day and ara C at a high dose over 2 hours every 12 hours for 4 doses (Days 2 and 3).

Citrovorum factor (leucovorin), an antidote for side effects of methotrexate, will be given by vein or by mouth for 2 3 days (Day 2 and on). Pegfilgrastim will be given as in Course 1 (24-72 hours after the chemotherapy is finished). The treatment to the brain inside the spinal fluid will be given as in Course 1 on Days 2 and 7.

The rest of the chemotherapy will switch between hyper CVAD (Courses 3, 5, and 7) and methotrexate/ara C (Courses 4, 6, and 8) to complete a total of 8 courses. Participants whose leukemia expresses CD20 will receive a total of 8 doses (2 per each of the 1st four courses) of rituximab.

After the 8 courses, patients with lymphoblastic lymphoma who had enlarged lymph glands in the mediastinum may receive radiation to the chest. Those participants not needing radiation, will proceed to monthly maintenance chemotherapy. This includes daily 6 mercaptopurine taken by mouth, weekly methotrexate by vein or mouth, monthly vincristine by vein, and prednisone by mouth for 5 days every month. Participants with lymphoblastic lymphoma will start maintenance chemotherapy after finishing radiation.

Maintenance chemotherapy will be given for a total of 30 months, and will be interrupted by 2 periods of intensive chemotherapy courses. The first will be at six months into the maintenance program starting first with methotrexate by vein on Day 1 and asparaginase by vein on Day 2. These will be given weekly for four doses. The following month, participants will receive hyper CVAD (like Course 1). Participants will receive this sequence of 2 chemotherapy courses again 18 months into the maintenance program.

After two courses of therapy, the response to the treatment will be evaluated. If the leukemia or lymphoma is responding, the therapy will be continued. Participants will be taken off study if the leukemia or lymphoma starts to get worse.

After completion of treatment, participants will have a complete exam, including blood tests (about 8 teaspoons). If needed, a chest X ray or CT scan will be done. A bone marrow sample will be taken through a large needle. Patients will then return every 3 to 6 months for a checkup, including blood and bone marrow. X rays may be repeated if needed.

An Ommaya reservoir may also be placed surgically as a route to treat leukemia in the brain or to decrease the risk of leukemia in patients who have difficulty with the spinal treatments. An Ommaya reservoir is a tube inserted under the skin of the scalp that enters into the spinal fluid cavity of the brain.

Treatment will be given on an inpatient basis for the 8 intensive cycles of chemotherapy, or as indicated by the clinical condition. The maintenance treatments may be given as an outpatient.

This is an investigational study. All of the drugs are commercially available. Their use together in this study is investigational. About 200 patients will take part in this study. All will be enrolled at M. D. Anderson.

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

Criteria:

Inclusion Criteria:

1. Newly diagnosed, previously untreated ALL or lymphoblastic lymphoma, or having achieved CR with one course of induction chemotherapy.

2. Failure to one induction course of chemotherapy are eligible, but these patients will be analyzed separately.

3. All ages are eligible.

4. Zubrod performance less than or equal to 3

5. Adequate liver function (bilirubin 6. Adequate cardiac function as assessed by history and physical examination.

7. No active co-existing malignancy with life expectancy less than 12 months due to that malignancy.

Exclusion Criteria:

- None.

Susan O'Brien, M.D., Phone: 713-792-7543, Email: sobrien@mdanderson.org

UT MD Anderson Cancer Center, Houston, Texas 77030, United States; Recruiting
Susan O'Brien, M.D., Phone: 713-792-7543, Email: sobrien@mdanderson.org
Susan O'Brien, M.D., Principal Investigator

M.D. Anderson's Website

Starting date: November 2002
Last updated: August 13, 2010