Arsenic Trioxide, Ascorbic Acid, Dexamethasone, and Thalidomide in Myelofibrosis/Myeloproliferative Disorder
Arsenic Trioxide, Ascorbic Acid, Dexamethasone, and Thalidomide in Myelofibrosis/Myeloproliferative Disorder
RATIONALE: Drugs used in chemotherapy, such as arsenic trioxide and dexamethasone, work in
 different ways to stop the growth of cancer cells, either by killing the cells or by stopping
 them from dividing. Sometimes when chemotherapy is given, it does not stop the growth of
 cancer cells. The cancer is said to be resistant to chemotherapy. Giving ascorbic acid may
 reduce drug resistance and allow the cancer cells to be killed. Thalidomide may stop the
 growth of cancer cells by blocking blood flow to the cancer. Giving arsenic trioxide together
 with ascorbic acid, dexamethasone, and thalidomide may kill more cancer cells.

 PURPOSE: This phase II trial is studying how well giving arsenic trioxide together with
 ascorbic acid, dexamethasone, and thalidomide works in treating patients with chronic
 idiopathic myelofibrosis or myelodysplastic or myeloproliferative disorders.
OBJECTIVES:

 Primary

 -  Evaluate the efficacy (in terms of response rate) of arsenic trioxide, ascorbic acid,
 dexamethasone, and thalidomide in patients with chronic idiopathic myelofibrosis or
 myelodysplastic/myeloproliferative disorders.

 Secondary

 -  Determine the rate of disease progression or progression to acute leukemia in patients
 treated with this regimen.

 -  Assess improvement in bone marrow pathology (including degree of fibrosis, percentage of
 blasts, and resolution of cytogenetic abnormalities) in patients treated with this
 regimen.

 -  Determine time to response in patients treated with this regimen.

 -  Determine the reduction of spleen size in patients treated with this regimen.

 -  Measure clinical responses and quality of life in subgroups treated with this regimen.

 -  Determine the safety of this regimen in these patients.

 OUTLINE: This is an open-label, multicenter study.

 Patients receive arsenic trioxide IV over 1-2 hours for 5 days and oral ascorbic acid once
 daily for 5 days during week 1. Patients then receive arsenic trioxide and ascorbic acid
 twice a week in weeks 2-12. Patients also receive oral dexamethasone once daily for 5 days in
 weeks 1, 5, 9, and 12 and oral thalidomide once or twice daily in weeks 1-12. Courses repeat
 every 12 weeks in the absence of disease progression or unacceptable toxicity.

 Quality of life is assessed at baseline and after every course.

 After completion of study treatment, patients are followed periodically.

 PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.
DISEASE CHARACTERISTICS:

 -  Chronic idiopathic myelofibrosis or myelodysplastic/myeloproliferative disorders
 (MDS/MPD), including the following subtypes:

 -  Chronic idiopathic myelofibrosis (with extramedullary hematopoiesis)

 -  Chronic myelomonocytic leukemia (CMML)

 -  Atypical chronic myeloid leukemia

 -  MDS/MPD disease, unclassifiable

 -  MDS with ≥ 2+ fibrosis present in the bone marrow

 -  Patients with MPD must be negative by fluorescent in situ hybridization
 (FISH) for the BCR/ABL fusion gene

 PATIENT CHARACTERISTICS:

 -  ECOG performance status 0-2

 -  Life expectancy of at least 3 months

 -  Platelet count > 10,000/mm³

 -  Bilirubin ≤ 2.5 times upper limit of normal (ULN)

 -  SGOT and SGPT ≤ 2.5 times ULN

 -  Creatinine ≤ 1.5 times ULN

 -  Potassium ≥ 4.0 mEq/dL (supplemental electrolytes allowed)

 -  Magnesium > 1.8 mg/dL (supplemental electrolytes allowed)

 -  Absolute QTc interval < 460 msec

 -  Patients who have a QT > 460 after electrolyte repletion and discontinuation of
 other unessential QT-prolonging drugs will be excluded

 -  Negative pregnancy test

 -  Women of childbearing potential must use medically acceptable birth control (two
 methods of birth control or at least one highly active method and one additional
 effective method), starting 4 weeks prior to starting thalidomide, all through
 thalidomide therapy, and for 4 weeks after discontinuing thalidomide

 -  Male patients with reproductive potential must use a latex condom every time they have
 sex with a woman from the time that they start taking thalidomide, all through
 thalidomide therapy, and for 4 weeks after discontinuing thalidomide

 -  No sperm or blood donation during study treatment

 -  Must be willing and able to comply with the FDA-mandated System for Thalidomide
 Educational Prescribing and Safety (S.T.E.P.S™) program

 -  No other serious medical condition, laboratory abnormality, or psychiatric illness
 that, in the view of the treating physician, would place the patient at an
 unacceptable risk if he or she were to participate in the study or would prevent that
 person from giving informed consent

 -  No preexisting neurotoxicity/neuropathy ≥ grade 2

 -  Not pregnant or nursing

 -  No cardiac conduction defects

 -  No unstable angina

 -  No myocardial infarction within the past 6 months

 -  No congestive heart failure of any cause

 -  No New York Heart Association class II or greater

 -  No other significant underlying cardiac dysfunction

 -  No prior malignancy in the 3 years before treatment in this study (other than
 curatively treated carcinoma in situ of the cervix or nonmelanoma skin cancer)

 -  No sulfa allergy that would interfere with administration of trimethoprim
 sulfamethoxazole prophylaxis

 -  Patients with sulfa allergies who could instead receive pentamidine prophylaxis
 also will be excluded

 -  Patients with sulfa allergies who can instead receive atovaquone may be included

 PRIOR CONCURRENT THERAPY:

 -  At least 4 weeks since prior investigational or approved therapy for this disease

 -  No growth factors within 1 week of study enrollment

 -  No other concurrent cytotoxic drugs or other investigational agents