OBJECTIVES:

Primary

• Determine the maximum tolerated dose of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) and bortezomib in patients with relapsed or refractory acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic lymphoma, or non-Hodgkin's lymphoma.
• Determine the toxic effects and dose-limiting toxicity of this regimen in these patients.

Secondary

• Determine the pharmacokinetics of 17-AAG alone and in combination with bortezomib in these patients.
• Correlate FLT3 mutational status with leukemic cell response in patients with AML treated with this regimen.
• Correlate Bcl-2 over-expression with response in patients treated with this regimen.

OUTLINE: This is a dose-escalation study. Patients are stratified according to diagnosis (acute myeloid leukemia [AML] or acute lymphoblastic leukemia vs chronic lymphoctyic leukemia or non-Hodgkin's lymphoma [NHL]).

Patients receive 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) IV over 1-6 hours on days 1, 4, 8, and 11 and bortezomib IV over 3-5 seconds on days 4, 8, and 11 of course 1 and on days 1, 4, 8, and 11 of all subsequent courses. Treatment repeats every 21 days for 3-12 courses provided patient is receiving clinical benefit. Patients achieving objective response may discontinue therapy to undergo stem cell transplantation.

Cohorts of 3-6 patients with receive escalating doses of 17-AAG and bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. After the MTD is determined, an additional 20 patients (10 per stratum with AML or follicular NHL) are enrolled and receive 17-AAG and bortezomib as above at the MTD.

PROJECTED ACCRUAL: A total of 56-74 patients (36-54 [18-27 per stratum] who undergo dose escalation and 20 [10 per stratum] treated at the maximum tolerated dose) will be accrued for this study within 1-2 years.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed diagnosis of 1 of the following hematologic malignancies:

  • Acute myeloid leukemia or acute lymphoblastic leukemia

    • Not a candidate for potentially curative therapy
    • WBC %u2264 10,000/mm^3 OR WBC %u2264 40,000/mm^3 that is stable for 5 days (hydroxyurea allowed)
    • No acute promyelocytic leukemia

  • Non-Hodgkin's lymphoma (NHL), including 1 of the following subtypes:

    • Small lymphocytic lymphoma
    • Marginal zone lymphoma
    • Lymphoplasmacytic lymphoma
    • Follicular lymphoma
    • Mantle cell lymphoma
    • Diffuse large B-cell lymphoma
    • Anaplastic large cell lymphoma
    • Peripheral T-cell lymphoma
    • Extranodal NK/T cell lymphoma (nasal and nasal type)
    • Enteropathy-type T-cell lymphoma
    • Hepatosplenic T-cell lymphoma
    • Angioimmunoblastic T-cell lymphoma
    • Subcutaneous panniculitis-like T-cell lymphoma
  • Chronic lymphocytic leukemia (CLL)

• Patients with NHL or CLL must meet the following criteria:

  • Ineligible for, or refused potentially curative stem cell transplantation
  • Transformed lymphoma/Richter's transformation, defined as the transformation of low-grade lymphoma, including follicular lymphoma, CLL, or small lymphocytic lymphoma to high-grade lymphoma (i.e., diffuse large cell lymphoma) allowed at time of transformation
  • Evidence of %u2265 50% bone marrow involvement at the time of enrollment OR tumor tissue accessible for biopsy (for patients enrolled after the maximum tolerated dose [MTD] is determined)
  • Absolute neutrophil count %u2265 1,000/mm^3
  • Platelet count %u2265 100,000/mm^3
• Relapsed or refractory disease
• Willing to undergo serial bone marrow biopsy (for patients enrolled after the MTD is determined)
• No untreated or active CNS leukemia or lymphoma

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin %u2264 1.5 mg/dL
• AST and ALT %u2264 2.5 times upper limit of normal

Renal

• Creatinine %u2264 2.0 mg/dL

Cardiovascular

• No uncontrolled cardiac disease
• No New York Heart Association class III-IV symptomatic congestive heart failure
• No unstable angina pectoris
• No serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation > 3 beats in a row) within the past 6 months
• No other uncontrolled cardiac arrhythmia or requiring antiarrhythmic drugs
• No myocardial infarction within the past year
• No active ischemic heart disease within the past year
• No congenital long QT syndrome
• No left bundle branch block
• QTc %u2265 450 msec (for men) or 470 (for women) on ECG/EKG
• No history of LVEF < 50% by MUGA or echocardiogram
• Resting ejection fraction %u2265 50% by MUGA or echocardiogram
• No prior history of cardiac toxicity after receiving anthracycline therapy (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, or mitoxantrone hydrochloride)

Pulmonary

• No uncontrolled pulmonary disease
• No symptomatic pulmonary disease requiring oxygen or medications
• DLCO (i.e., oxygen diffusion capacity) %u2265 80% on pulmonary function testing
• Resting and exercise oxygen saturation %u2265 90% by pulse oximetry

• No ongoing pulmonary symptoms %u2265 grade 2 including any of the following:

  • Dyspnea on or off exertion
  • Paroxysmal nocturnal dyspnea
  • Significant pulmonary disease including chronic obstructive or restrictive pulmonary disease
  • No prior history of pulmonary toxicity after bleomycin or carmustine
• No Medicare requirement for home oxygen (e.g., Resting O_2 saturation %u2265 90% or desaturation to %u2265 90% with exertion)

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No preexisting sensory or motor peripheral neuropathy %u2265 grade 2
• No history of allergic reaction to eggs
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• No other uncontrolled illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• Prior stem cell transplantation for relapsed or refractory disease allowed
• At least 2 weeks since prior immunotherapy and recovered

Chemotherapy

• See Disease Characteristics
• At least 2 weeks since prior chemotherapy (excluding hydroxyurea) and recovered
• No other concurrent chemotherapy

Endocrine therapy

• No concurrent routine corticosteroids except for treatment of other medical problems (e.g., pulmonary, rheumatologic, or adrenal disorders)

Radiotherapy

• At least 2 weeks since prior radiotherapy and recovered
• No prior radiotherapy that potentially included the heart in the field (e.g., mantle)
• No prior history of chest radiation
• No concurrent palliative radiotherapy

Surgery

• Not specified

Other

• At least 2 weeks since prior investigational therapy
• Prior bortezomib allowed
• No other concurrent commercial or investigational agents or therapies for the malignancy