3-AP and Fludarabine in Treating Patients With Myeloproliferative Disorders, Chronic Myelomonocytic Leukemia, or Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia

National Cancer Institute (NCI)

Status and phase

Completed

Phase 2

Conditions

Polycythemia Vera

Primary Myelofibrosis

Philadelphia Chromosome Negative Chronic Myelogenous Leukemia

Chronic Eosinophilic Leukemia

Blastic Phase Chronic Myelogenous Leukemia

Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative

Relapsing Chronic Myelogenous Leukemia

Essential Thrombocythemia

Accelerated Phase Chronic Myelogenous Leukemia

Chronic Myelomonocytic Leukemia

Treatments

Drug: fludarabine phosphate

Drug: triapine

Procedure: laboratory biomarker analysis

Study type

Interventional

Funder types

NIH

Identifiers

NCT00381550

U01CA070095 (U.S. NIH Grant/Contract)

P30CA006973 (U.S. NIH Grant/Contract)

7704 (Other Identifier)

NCI-2009-00209 (Registry Identifier)

J0638 (Other Identifier)

Details and patient eligibility

About

This phase II trial is studying how well giving 3-AP together with fludarabine works in treating patients with myeloproliferative disorders (MPD), chronic myelomonocytic leukemia (CMML), or accelerated phase or blastic phase chronic myelogenous leukemia. Drugs used in chemotherapy, such as 3-AP and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. 3-AP may help fludarabine work better by making cancer cells more sensitive to the drug. 3-AP and fludarabine may also stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving 3-AP together with fludarabine may kill more cancer cells.

Full description

OBJECTIVES:

I. Determine the efficacy of 3-AP (Triapine®) followed by fludarabine phosphate in patients with myeloproliferative disorders or chronic myelomonocytic leukemia in aggressive phase or transformation or chronic myelogenous leukemia in accelerated phase or blast crisis.

II. Determine the toxicity of this regimen in these patients. III. Determine, preliminarily, the effect of this regimen on circulating leukemic cell genetics in these patients.

Outline: This is an open-label study.

Patients receive 3-AP (Triapine®) IV over 4 hours followed by fludarabine phosphate IV over 30 minutes on days 1-5. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow and/or peripheral blood collection at baseline and periodically during study treatment for molecular analysis of Janus kinase 2 (JAK2) mutations, GATA-1 mutations, and expression of the death-inducer-obliterator (Dido) genes on chromosome 20q.

After completion of study treatment, patients are followed periodically.

Enrollment

35 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Criteria:

Not pregnant or nursing
Histopathologically confirmed diagnosis of 1 of the following:
- Myeloproliferative disorders (MPDs) in aggressive phase or transformation
- CML in accelerated phase or blast crisis
- Chronic myelomonocytic leukemia in aggressive phase (5-19% bone marrow blasts) or transformation (> 20% bone marrow blasts)
Myeloproliferative disorders (MPDs) in aggressive phase or transformation, including the following:
- Polycythemia vera (PV)
- Essential thrombocythemia (ET)
- Myelofibrosis with myeloid metaplasia
- Hypereosinophilic syndrome
- Atypical (Philadelphia chromosome negative) chronic myelogenous leukemia (Ph- CML)
Patients with aggressive phase MPD (PV, ET, or Ph- CML) must meet ≥ 1 of the following criteria:
- Marrow blasts > 5%
- Peripheral blood blasts plus progranulocytes > 10%
- New onset or increasing myelofibrosis
- New onset or > 25% increase in hepatomegaly or splenomegaly
- New onset constitutional symptoms (fever, weight loss, splenic pain, bone pain)
Multilineage bone marrow failure
Ineligible for established curative regimens, including stem cell transplantation
ECOG performance status 0-2
Negative pregnancy test
Fertile patients must use effective contraception
No chronic toxicity from prior chemotherapy > grade 1
No history of severe coronary artery disease
Creatinine normal OR creatinine clearance >= 60 mL/min
AST and ALT =< 2.5 times normal
Bilirubin =< 2.0 mg/dL unless due to leukemia, Gilbert's syndrome, or hemolysis
No arrhythmias (other than atrial flutter or fibrillation) requiring medication
No uncontrolled congestive heart failure
No dyspnea at rest or with minimal exertion
No severe pulmonary disease requiring supplemental oxygen
No history of allergic reactions attributed to compounds of similar chemical or biological composition to 3-AP (Triapine®) and/or fludarabine phosphate
No other life-threatening illness
No history of mental deficits and/or psychiatric illness that would preclude study compliance
No more than 4 prior induction regimens (3 cytotoxic chemotherapy regimens)
At least 3 weeks since prior myelosuppressive cytotoxic agents (6 weeks for mitomycin C or nitrosoureas) and recovered
At least 1 week since prior nonmyelosuppressive treatment
At least 48 hours since prior noncytotoxic agents for peripheral blood leukemic cell count control, including but not limited to the following:
- Hydroxyurea
- Imatinib mesylate
- Interferon
- Mercaptopurine
- Cyclophosphamide
At least 2 weeks since prior and no concurrent radiotherapy to treat cancer
At least 1 week since prior biologic therapy, including hematopoietic growth factors (e.g., epoetin alfa, darbepoetin alfa, filgrastim [G-CSF], sargramostim [GM-CSF], interleukin-3, or interleukin-11)
No other concurrent chemotherapy to treat cancer
No concurrent immunotherapy to treat cancer
No known glucose-6-phosphate dehydrogenase [G6PD) deficiency (G6PD screening required for high-risk groups (i.e., patients of African, Asian, or Mediterranean origin/ancestry)]
No active heart disease
No concurrent myeloid growth factors
No active uncontrolled infection (Infections under active treatment and controlled with antibiotics are allowed)
No chronic hepatitis