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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase II Trial of Triapine (NSC #663249, 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbone) Plus Fludarabine (NSC #312887, Fludarabine Monophosphate) in Adults With Aggressive Myeloproliferative Disorders (MPDs) Including Chronic Myelomonocytic Leukemia (CMML) and Chronic Myelogenous Leukemia in Accelerated Phase (CML-AP) or Blast Crisis (CML-BC)

Conditions
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Chronic Eosinophilic Leukemia, Accelerated Phase Chronic Myelogenous Leukemia, Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Blastic Phase Chronic Myelogenous Leukemia, Chronic Myelomonocytic Leukemia, Essential Thrombocythemia, Philadelphia Chromosome Negative Chronic Myelogenous Leukemia, Polycythemia Vera, Primary Myelofibrosis, Relapsing Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: fludarabine phosphate
* Drug: triapine
* Procedure: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Drug: triapine<br>* Given IV<br>* Other names: OCX-191;Procedure: laboratory biomarker analysis<br>* Correlative study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate Including Complete Response, Partial Response, and Hematological Improvement Assessed by Blood Cell Counts, Number of Blasts in Bone Marrow, and Clinical Evaluation | Bone marrow aspiration and biopsies were performed prior to treatment, during week 3 of the first cycle, at the time of hematologic recovery from all cycles of therapy (defined as neutrophil count >500/mm3 and platelets >20,000/mm3 independently of transfusion), or at any time that leukemia regrowth was suspected. The overall response rate was defined as complete remission, partial remission, or hematologic improvement, lasting for ≥30 days. Given the different subsets of diseases, standardized response criteria were used for CMML (the Myelodysplastic Syndrome International Working Group criteria),33 CMML transforming to acute myeloid leukemia (standard AML response criteria) , accelerated MPN (Giles et al.), and transformation of MPN to secondary AML (Mascarenhas et al.). | Up to 4 years | 
| Incidence of Grade 3 or 4 Drug-related Non-hematologic Toxicity as Assessed by NCI CTCAE v3.0 |  | Up to 4 years |