Leukemia, Myelodysplastic/Myeloproliferative Diseases, Myelodysplastic Syndromes
Conditions
Keywords
accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, refractory chronic lymphocytic leukemia, recurrent adult acute lymphoblastic leukemia, prolymphocytic leukemia, refractory anemia with excess blasts, chronic myelomonocytic leukemia, recurrent adult acute myeloid leukemia, secondary acute myeloid leukemia, adult acute minimally differentiated myeloid leukemia (M0), adult acute monocytic leukemia (M5b), adult acute erythroid leukemia (M6), adult acute megakaryoblastic leukemia (M7), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myelomonocytic leukemia (M4), adult acute monoblastic leukemia (M5a), adult acute promyelocytic leukemia (M3), adult acute eosinophilic leukemia, adult acute basophilic leukemia, atypical chronic myeloid leukemia, myelodysplastic/myeloproliferative disease, unclassifiable, adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with t(15;17)(q22;q12)
Brief summary
RATIONALE: Drugs used in chemotherapy, such as fludarabine, work in different ways to stop cancer cells from dividing so they stop growing or die. 3-AP may help fludarabine kill more cancer cells by making them more sensitive to the drug. PURPOSE: This phase I trial is studying the side effects and best dose of fludarabine when given together with 3-AP in treating patients with relapsed or refractory acute leukemia, chronic leukemia, or high-risk myelodysplastic syndrome.
Detailed description
OBJECTIVES: * Determine the feasibility and tolerability of 3-AP (Triapine\^® ) followed by fludarabine in patients with relapsed or refractory acute or chronic leukemia or high-risk myelodysplastic syndromes. * Determine the toxic effects of this regimen in these patients. * Determine the maximum tolerated dose of this regimen in these patients. OUTLINE: This is a multicenter, dose-escalation study of fludarabine. Patients are stratified according to disease (acute leukemias and myelodysplastic syndromes \[MDS\] vs chronic lymphocytic leukemia and prolymphocytic leukemia). Patients are assigned to 1 of 2 treatment groups. * Group 1 (chronic lymphocytic leukemia or prolymphocytic leukemia): Patients receive 3-AP (Triapine\^®) IV over 4 hours and fludarabine IV over 30 minutes on days 1-5. Cohorts of 3-6 patients receive escalating doses of fludarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, 10 additional patients are treated at that dose level. * Group 2 (acute leukemias or MDS): Patients receive 3-AP IV continuously over 24 hours on day 1. Beginning within 4 hours after completion of 3-AP, patients receive fludarabine IV over 30 minutes on days 2-6. In both groups, treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. PROJECTED ACCRUAL: A total of 3-34 patients will be accrued for this study.
Interventions
DRUGfludarabine phosphate
DRUGtriapine
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Primary purpose
TREATMENT
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed diagnosis of 1 of the following: * High-risk myelodysplastic syndromes (MDS), including refractory anemia with excess blasts and chronic myelomonocytic leukemia * International Prognostic Scoring System (IPSS) score at least 1.5 based on the following: * More than 10% marrow blasts * Cytopenias in at least 2 lineages * Adverse cytogenetics * Acute myeloid leukemia (AML) * All subtypes, including MDS/AML and treatment-related (secondary) AML * Acute lymphoblastic leukemia * Acute progranulocytic leukemia * Ineligible for arsenic therapy * Chronic myelogenous leukemia * Accelerated phase or blastic crisis * Chronic lymphocytic leukemia * Prolymphocytic leukemia * Received or ineligible for established curative regimens, including stem cell transplantation * Acute and chronic leukemias must be relapsed and/or refractory with progressive disease since last therapy PATIENT CHARACTERISTICS: Age * 18 and over Performance status * ECOG 0-2 Life expectancy * Not specified Hematopoietic * No history of hemolytic anemia grade 2 or greater * 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) Hepatic * SGOT and SGPT no greater than 2.5 times normal * Bilirubin no greater than 2 mg/dL * No chronic hepatitis Renal * Creatinine normal OR * Creatinine clearance at least 60 mL/min Cardiovascular * No active heart disease * No myocardial infarction within the past 3 months * No severe coronary artery disease * No arrhythmias (other than atrial flutter or fibrillation) requiring medication * No uncontrolled congestive heart failure Pulmonary * No dyspnea at rest or with minimal exertion * No severe pulmonary disease requiring supplemental oxygen Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No neuropathy grade 2 or greater * No active uncontrolled infection * Infections under active treatment and controlled by antibiotics are allowed * No other life-threatening illness * No psychiatric illness that would preclude study compliance PRIOR CONCURRENT THERAPY: Biologic therapy * See Disease Characteristics * At least 1 week since prior hematopoietic growth factor (e.g., epoetin alfa, filgrastim \[G-CSF\], sargramostim \[GM-CSF\], interleukin-3, and interleukin-11) * No concurrent immunotherapy Chemotherapy * Recovered from prior chemotherapy (no greater than grade 1 chronic toxic effects) * At least 72 hours since prior hydroxyurea * At least 3 weeks since prior myelosuppressive cytotoxic agents (6 weeks for mitomycin or nitrosoureas) * No more than 12 prior courses of fludarabine * No more than 3 prior cytotoxic chemotherapy regimens * No other concurrent chemotherapy Endocrine therapy * Not specified Radiotherapy * At least 2 weeks since prior radiotherapy * No concurrent radiotherapy Surgery * Not specified Other * At least 1 week since prior non-myelosuppressive treatment * No more than 4 prior induction regimens * No other concurrent therapy
Countries
United States
Outcome results
None listed