Imatinib Mesylate, Busulfan, Fludarabine, and Antithymocyte Globulin for CML Patients

Study Description

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Brief Summary:

Primary Objective:

To estimate the probability of molecular complete remission at one year for the described sequential treatment approach, with nonablative hematopoietic transplantation, post transplant imatinib mesylate and donor lymphocyte infusion, in patients with Ph-positive Chronic Myelogenous Leukemia (CML) not in blastic transformation.

Secondary Objective:

Response to post transplant Imatinib mesylate therapy for 12 weeks as treatment of residual disease, response to donor lymphocyte infusion (DLI) for residual disease following imatinib mesylate therapy, as well as engraftment, toxicity, disease free survival and survival, effect of busulfan pharmacokinetics on study outcome.

Condition or disease	Intervention/treatment	Phase
Leukemia	Drug: Imatinib Mesylate; Drug: Fludarabine (Fludara); Drug: Busulfan; Drug: Antithymocyte Globulin (ATG); Drug: Tacrolimus; Drug: Methotrexate; Procedure: Donor lymphocyte infusion (DLI); Procedure: Stem Cell Transplant	Phase 2

Detailed Description:

Patients will have blood and bone marrow tests performed as well as chest and sinus X-rays and tests of their heart and lung function. Approximately 5 tablespoons of blood will be drawn.

All patients in this study will receive imatinib mesylate by mouth for 9 days, unless the patient is known to be allergic or have symptomatic intolerance to the drug, or if the leukemia has failed to respond to imatinib. Fludarabine 40 mg/m2 by vein for 4 days (days -5 to -2), busulfan 130 mg/m2 by vein for 2 days (days -3 and -2), and ATG (Antithymocyte Globulin) 2.5 mg/kg by vein for 3 days (-3,-2 and -1).

Patients will then receive the donor bone marrow or blood stem cells by vein over approximately one hour on day 0.

After the infusion of the donor cells, you will receive immunosuppressive therapy with tacrolimus and methotrexate to decrease the risk of developing graft-vs-host disease (GvHD).

Patients will need frequent blood tests to monitor their counts and blood chemistries. This is generally done daily while in hospital and at least twice per week for the first 100 days post transplant. You may need frequent blood transfusions and may have to be admitted to the hospital to receive antibiotics if they develop fever. Bone marrow will be examined frequently beginning four weeks after treatment to evaluate response to treatment; Blood and bone marrow exams are to be performed at one, two three, six, 12 and 18 months post transplant and yearly thereafter for 5 years. To collect a bone marrow sample, an area of the hip or chest bone is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle.

Patients in whom treatment produces a remission, in which no sign of the leukemia can be detected, will receive no further therapy unless the leukemia recurs. Patients with evidence of leukemia after 3 months from the transplant will receive additional treatment with imatinib mesylate; those with detectable leukemia after an additional 3 months may receive an infusion of immune cells from the transplant donor.

If there is evidence of leukemia after the transplant, you will receive additional treatment with imatinib mesylate. If leukemia cells can still be detected, additional donor immune cells will be given to you by vein.

Patients are considered on the study for 5 years after the transplant.

A total of 90 patients will take part in this study. All will be enrolled at M. D. Anderson.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	42 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Imatinib Mesylate, Busulfan, Fludarabine, Antithymocyte Globulin and Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia
Study Start Date :	February 2003
Actual Primary Completion Date :	November 2009
Actual Study Completion Date :	November 2009

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Imatinib, Busulfan, Fludara + Antithymocyte Globulin; Oral Imatinib Mesylate 400 mg twice a day for 9 Days; Busulfan 130 mg/m^2 by vein (IV) daily for 2 Days; Fludara 40 mg/m^2 IV daily for 4 Days; Antithymocyte Globulin (ATG) 2.5 mg/kg IV daily for 3 Days; Tacrolimus levels maintained between 5-15 ng/dl, Day -2 to Day 180; Methotrexate 5 mg/m2 on days 1, 3, 6 and 11; and Donor bone marrow or blood stem cells infused on day 0 with possible donor lymphocyte infusion (DLI) for progressive disease.

Drug: Imatinib Mesylate; 400 mg by mouth twice daily for 9 Days; Other Names: Gleevec; STI571 Drug: Fludarabine (Fludara); 40 mg/m^2 by vein daily for 4 Days; Other Names: Fludarabine Phosphate; Fludara; Fludarabine Drug: Busulfan; 130 mg/m^2 by vein daily for 2 Days; Other Names: Busulfex; Myleran Drug: Antithymocyte Globulin (ATG); 2.5 mg/kg by vein daily for 3 Days; Other Names: ATG; Thymoglobulin Drug: Tacrolimus; Tacrolimus levels maintained between 5-15 ng/dl, first as continuous IV infusion, and converted to oral every 12 hour dosing as tolerated. Starting day -2 until day 180.; Other Name: Prograf Drug: Methotrexate; 5 mg/m2 on days 1, 3, 6 and 11. Procedure: Donor lymphocyte infusion (DLI); Infusion of lymphocytes from the original bone marrow donor by vein if relapse after >4 weeks of imatinib.; Other Names: buffy coat fusion; donor leukocyte infusion; apheresis; donor immune cell infusion Procedure: Stem Cell Transplant; Infusion of donor bone marrow or blood stem cells by vein over approximately one hour on day 0.; Other Names: stem cell infusion; stem cell transplantation; ALLOGENEIC STEM CELL TRANSPLANTATION; HSCT; hematopoietic stem cell transplant; Bone Marrow transplant; PBSC; Peripheral Blood Stem Cell

Outcome Measures

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Primary Outcome Measures :

1. Number of Participants in Complete Molecular Remission at 1 Year [ Time Frame: Baseline to 1 year ]
   Participants at 1 year in molecular remission, post transplant, post imatinib mesylate and donor lymphocyte infusion (DLI). Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests (this test is most commonly used in clinical trials).

Secondary Outcome Measures :

1. Participants' With mCR Response to Post Transplant Imatinib Mesylate Therapy [ Time Frame: 1 Year ]
   Number of participants with response of molecular complete remission (mCR) to Imatinib Mesylate therapy as treatment for residual disease after transplant. Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests.
2. Participants' With mCR Response to Post Transplant DLI [ Time Frame: 1 year ]
   Number of participants with response of molecular complete remission (mCR) to DLI as treatment for residual disease after transplant. Molecular remission is a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive polymerase chain reaction (PCR) tests.

Eligibility Criteria

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Ages Eligible for Study:	up to 70 Years (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Diagnosis of Ph+ chronic myelogenous leukemia (CML) in first chronic phase without a complete hematologic response after 3 months of Imatinib mesylate therapy, or >=35% Ph+ cells despite > 6 months of Imatinib mesylate treatment, or after disease progression from a complete or partial response. Any patient with accelerated phase or blast crisis who achieves a subsequent chronic phase is eligible. Patients must have an HLA matched related or unrelated donor or one antigen mismatched related donor.
2. Patients should be less than 70 years of age. Patients less than 30 years of age who achieve a hematologic remission with imatinib therapy are eligible regardless of cytogenetic response.
3. Patients are stratified as Group 1: First chronic phase, Group 2 Accelerated phase or blast crisis that achieved a hematologic remission with imatinib mesylate-based treatment.

Exclusion Criteria:

1. Zubrod Performance Scale (PS) >=2, uncontrolled infection, Creatinine > 2.0 mg/dl; Ejection fraction < 40%; Carbon Monoxide Diffusing Capacity (DLCO) < 45% of predicted; Serum bilirubin > 2 gm/dl; GPT (Glutamic-pyruvic transaminase) or GOT (glutamic-oxaloacetic transaminase)> 3 times normal values. Patients should not be human immunodeficiency virus (HIV) seropositive or pregnant.
2. Patients should not have progressed to accelerated phase or blast crisis while receiving imatinib mesylate containing therapy.

Contacts and Locations

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Locations

United States, Texas
UT MD Anderson Cancer Center
Houston, Texas, United States, 77030

Sponsors and Collaborators

M.D. Anderson Cancer Center

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Richard E. Champlin, MD	M.D. Anderson Cancer Center

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

The University of Texas M.D.Anderson Cancer Center 

Responsible Party:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT00499889 History of Changes
Other Study ID Numbers:	ID02-901
First Posted:	July 12, 2007
Results First Posted:	November 7, 2011
Last Update Posted:	April 23, 2012
Last Verified:	April 2012

Keywords provided by M.D. Anderson Cancer Center:

Chronic Myelogenous Leukemia; Allogeneic Stem Cell Transplantation; Leukemia; Imatinib Mesylate; Gleevec; Busulfan; Busulfex	Myleran; Fludarabine; ATG; STI571; Antithymocyte Globulin; Thymoglobulin

Additional relevant MeSH terms:

Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasms by Histologic Type; Neoplasms; Leukemia, Myeloid; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Methotrexate; Fludarabine phosphate; Tacrolimus; Imatinib Mesylate; Busulfan; Thymoglobulin; Antilymphocyte Serum	Vidarabine; Fludarabine; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents; Immunologic Factors