Bortezomib, Daunorubicin, and Cytarabine in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia

• Remission Induction Response [ Time Frame: 2 months ] [ Designated as safety issue: No ]

  Response was calculated according to Revised International Working Group (IWG) criteria for Acute myeloid leukemia (AML)

  A response was defined as the portion of participants who achieved a complete response (CR) or CR with incomplete platelet recovery(CRp) during induction.

  A CR is defined as those with > 20% cellularity of bone marrow biopsy, no presence of extramedullary leukemia for AML, <5 % myeloblast cells for bone marrow with peripheral blood and normal complete blood count (absolute neutrophils > 1000 mL and platelets >= 100,000 mL).

  A CRp is defined as a CR except platelets < 100,000 mL without need for transfusion.

• Participants Experiencing a Dose-limiting Toxicity (DLT) of Bortezomib When Administered in Combination With Intermediate-dose Cytarabine [ Time Frame: during consolidation cycle 1 (42 days) ] [ Designated as safety issue: Yes ]

  DLTs were considered only during the first cycle of consolidation therapy and included grade 3 or 4 sensory or autonomic neuropathy, persistent grade 4 thrombocytopenia or neutropenia at day 42 in the absence of AML,any grade 4 or 5 nonhematologic toxicity, and any grade 3 nonhematologic toxicity (excluding neuropathy and toxicities secondary to neutropenia and sepsis) that did not resolve to grade 2 by day 42 unless attributable to persistent or recurrent AML. Grade 4 anorexia (requiring total parenteral nutrition) and grade 4 fatigue (requiring bed rest) were not considered DLTs.

  Toxicity was graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grading scale is as follows: grade 1: mild; grade 2: moderate; grade 3: Severe; grade 4: Life Threatening; grade 5: Death.

• Remission induction response rate (complete response [CR] and CR with incomplete platelet recovery [CRp]) [ Designated as safety issue: No ]
• Maximum tolerated dose and dose-limiting toxicity of bortezomib when administered in combination with intermediate-dose cytarabine [ Designated as safety issue: Yes ]

• Disease-free Survival [ Time Frame: Duration of study (up to 10 years) ] [ Designated as safety issue: No ]
  Disease-free survival (DFS) was measured as the interval from achievement of CR until relapse or death, regardless of cause. DFS was estimated using the Kaplan Meier method.
• Overall Survival [ Time Frame: Duration of study (up to 10 years) ] [ Designated as safety issue: No ]
  Overall survival (OS) as the interval from the on-study date until death. OS was estimated using the Kaplan Meier method.

• Toxicity as assessed by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
• Median disease-free survival [ Designated as safety issue: No ]
• Median overall survival [ Designated as safety issue: No ]

This phase II trial is studying the side effects and best dose of bortezomib when given together with daunorubicin and cytarabine and to see how well it works in treating older patients with previously untreated acute myeloid leukemia. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as daunorubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with combination chemotherapy may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To define the remission induction response rate (complete response [CR] and CR with incomplete platelet recovery [CRp]) in older patients with previously untreated acute myeloid leukemia treated with induction therapy comprising bortezomib in combination with daunorubicin hydrochloride and cytarabine.

II. To define the maximum tolerated dose of bortezomib when administered in combination with intermediate-dose cytarabine after induction therapy.

SECONDARY OBJECTIVES:

I. To describe the disease-free survival of patients treated with this regimen.

II. To describe the overall survival of patients treated with this regimen.

III. To evaluate the treatment-related toxicities in these patients.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Doses of bortezomib are escalated during remission consolidation therapy.

• Remission induction therapy:

  • Remission induction course 1: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11; daunorubicin hydrochloride IV on days 1-3; and cytarabine IV continuously over 168 hours on days 1-7.

After completion of remission induction course 1, patients undergo bone marrow aspiration and biopsy for evaluation of response. Patients achieving a complete response (CR) or partial response (PR) proceed to remission consolidation therapy. Patients achieving a CR with incomplete platelet recovery (CRp) proceed to remission consolidation therapy after platelet counts recover. Patients with persistent leukemia (≥ 20% bone marrow cellularity and ≥ 5% bone marrow myeloblasts) proceed to remission induction course 2.

• Remission induction course 2: Patients receive bortezomib IV over 3-5 seconds on days 1 and 4; daunorubicin hydrochloride IV on days 1 and 2; and cytarabine IV continuously over 120 hours on days 1-5.

After completion of remission induction course 2, patients undergo bone marrow aspiration and biopsy for evaluation of response. Patients achieving a CR or PR proceed to remission consolidation therapy. Patients achieving a CRp proceed to remission consolidation therapy after platelet counts recover. Patients with residual leukemia who do not meet the criteria for PR are removed from the study.

• Remission consolidation therapy: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and intermediate-dose cytarabine IV over 3 hours on days 1-5. Patients then undergo bone marrow aspiration and biopsy for evaluation of response. Patients achieving a CR or who demonstrate continuing CR receive a second course of remission consolidation therapy beginning 2-4 weeks after blood counts recover.

After completion of study therapy, patients are followed every 2 months for 2 years, every 3 months for 2 years, and then annually for up to 10 years.

• Drug: bortezomib
  Induction: 1.3 mg/sq m IV infusion Days 1,4,8,11 (Days 1, 4 only if 2nd induction) Consolidation: 0.7 OR 1 OR 1.3 mg/sq m IV infusion Days 1,4,8,11
• Drug: cytarabine
  Induction: 100 mg/sq m/day CIVI Days 1-7 (Days 1-5 only if 2nd induction) Consolidation: 2 g/sq m/day IV infusion Days 1-5
• Drug: daunorubicin hydrochloride
  Induction: 60 mg/sq m IV infusion Days 1-3 (Days 1-2 if 2nd induction)

DISEASE CHARACTERISTICS:

• Unequivocally histologically confirmed acute myeloid leukemia (AML)

  • At least 20% blasts in the bone marrow based on WHO criteria
  • No acute promyelocytic leukemia (M3)
• Antecedent hematologic disorder or myelodysplastic syndromes allowed provided the patient did not receive cytotoxic chemotherapy, including azacitidine and decitabine, for their pre-leukemic disorder
• Concurrent enrollment on CALGB-8461 required

PATIENT CHARACTERISTICS:

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No ataxia, cranial neuropathy, or peripheral neuropathy ≥ grade 2
• LVEF ≥ 40% by ECHO or MUGA scan
• No signs or symptoms of congestive heart failure
• DLCO ≥ 50% (corrected for hemoglobin)

PRIOR CONCURRENT THERAPY:

• No prior therapy for leukemia or pre-leukemic disorders, except for the following:

  • Emergency leukapheresis
  • Emergency treatment for hyperleukocytosis with hydroxyurea
  • Cranial radiotherapy for CNS leukostasis (one dose only)
  • Growth factor/cytokine support

• No other concurrent chemotherapy, except for the following:

  • Steroids administered for adrenal failure, hypersensitivity reactions, or septic shock
  • Hormones administered for non-disease-related conditions (e.g., insulin for diabetes or estrogens or progestins for gynecologic indications)
• No concurrent palliative radiotherapy