A Phase I And Pharmacological Trial Of 17-Allylamino -17-demethoxygeldanamycin (17-AAG) And Cytarabine In Refractory Leukemia And Myelodysplastic Syndrome

Inclusion Criteria:

- Diagnosis of 1 of the following:

- Acute myeloid leukemia, except acute promyelocytic leukemia (M3 disease),
meeting 1 of the following criteria:

- Failed to achieve complete remission (CR) after initial induction therapy
regimen*

- First relapse within 1 year of initial CR

- Failed re-induction therapy at first or second relapse

- Second or third relapse after completing ≤ 3 different induction therapy
regimens

- Antecedent hematologic disorder (myelodysplastic syndromes [MDS], chronic
myeloproliferative disease, or chronic myelomonocytic leukemia [CMML])

- Received prior chemotherapy for a non-hematologic malignancy

- High-risk cytogenetic abnormalities (abnormalities of chromosome 5, 7, 8,
or 11 OR ≥ 3 karyotypic abnormalities)

- Acute lymphoblastic leukemia, meeting 1 of the following criteria:

- Failed to achieve CR after initial induction therapy regimen

- First relapse within 1 year of initial CR

- Failed re-induction therapy at first or second relapse

- Second or third relapse after completing ≤ 3 different induction therapy
regimens

- Chronic myelogenous leukemia, meeting the following criteria:

- Accelerated OR blast phase (> 10% increase in the blast percentage in bone
marrow)

- Failed prior imatinib mesylate

- No more than 1 prior chemotherapy regimen in addition to imatinib
mesylate

- CMML, meeting the following criteria:

- More than 10% increase in blast percentage AND organ infiltration OR
impending marrow failure as evidenced by cytopenia

- No t(5;12) by cytogenetics (unless failed prior trial of imatinib mesylate)

- High-grade MDS, defined as > 10% blasts on marrow cellularity (refractory anemia
with excess blasts in transformation) OR International Prognostic Scoring System
MDS prognostic score > 1.5

- Not a candidate for allogenic bone marrow transplantation* from a related sibling
donor (i.e., HLA-identical sibling)

- No known standard or potentially curative therapy exists or is capable of extending
life expectancy

- No clinical symptoms suggesting CNS leukemia

- Performance status - ECOG 0-2

- At least 60 days

- See Disease Characteristics

- Bilirubin ≤ 1.5 times upper limit of normal (unless attributed to underlying disease)

- Creatinine clearance ≥ 60 mL/min

- No New York Heart Association class III-IV heart failure

- No myocardial infarction within the past year

- LVEF ≥ 40% by MUGA

- No cardiac symptoms ≥ grade 2

- No uncontrolled dysrhythmia requiring medication

- No poorly controlled angina

- QTc ≤ 450 msec for men and ≤ 470 msec for women

- No congenital long QT syndrome

- No left bundle branch block

- No ischemic heart disease within the past 6 months

- No history of cardiac toxicity after treatment with anthracyclines (e.g., doxorubicin
hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or
carmustine

- No other significant cardiac disease

- No active uncontrolled infection

- No history of serious allergic reaction to eggs

- No known HIV infection or AIDS (with or without highly active antiretroviral
treatment)

- DLCO > 80%

- No pulmonary symptoms ≥ grade 2

- No symptomatic pulmonary disease requiring medication including any of the following:

- Dyspnea on or off exertion

- Paroxysmal nocturnal dyspnea

- Significant pulmonary disease (e.g., chronic obstruction/restrictive pulmonary
disease)

- No oxygen requirement

- No home oxygen that meets the medicare requirement

- No history of pulmonary toxicity after treatment with anthracyclines (e.g.,
doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride,
bleomycin, or carmustine

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No psychosis

- No other serious underlying medical condition that would preclude study participation

- No prior allogeneic or autologous bone marrow transplantation

- No concurrent immunotherapy

- No concurrent biologic agents

- No concurrent gene therapy

- See Disease Characteristics

- Recovered from prior chemotherapy

- At least 48 hours since prior hydroxyurea for prevention of leukostasis

- No other concurrent chemotherapy

- At least 48 hours since prior glucocorticoids for prevention of leukostasis

- No prior radiotherapy that included the heart in the field (e.g., mantle) or chest

- No concurrent radiotherapy

- No concurrent drugs that may cause QTc prolongation

- No concurrent participation in another clinical trial involving a pharmacologic agent
for symptom control or therapeutic intent

- No other concurrent investigational drugs or therapy