Gemtuzumab Ozogamicin in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia

Gemtuzumab Ozogamicin (GO) Monotherapy Versus Standard Supportive Care for Previously Untreated AML in Elderly Patients Who Are Not Eligible for Intensive Chemotherapy: A Randomized Phase II/III Trial (AML-19) of the EORTC-LG and GIMEMA-ALWP

RATIONALE: Monoclonal antibodies such as gemtuzumab ozogamicin can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. It is not yet known whether gemtuzumab ozogamicin is more effective than standard supportive care in treating older patients who have acute myeloid leukemia.

PURPOSE: This randomized phase II/III trial is studying two different gemtuzumab ozogamicin regimens to see how well they work compared to standard supportive care in treating older patients with previously untreated acute myeloid leukemia.

OBJECTIVES:

• Compare the feasibility, toxicity, and antileukemic activity of two different dosing regimens of gemtuzumab ozogamicin (GO) vs standard supportive care in older patients with previously untreated acute myeloid leukemia who are not candidates for intensive chemotherapy. (phase II)
• Compare the efficacy and toxicity of the best dosing regimen of GO selected from phase II vs standard supportive care, in terms of overall survival, in these patients. (phase III)

OUTLINE: This is a randomized, open-label, multicenter phase II study followed by a phase III study. Patients are stratified according to age (61 to 75 vs 76 to 80 vs 81 and over), CD33-positivity of bone marrow blasts (< 20% vs 20-80% vs > 80% vs unknown), initial WBC before hydroxyurea administration (< 30,000/mm^3 vs ≥ 30,000/mm^3), WHO performance status (0-1 vs 2 vs 3-4), and participating center.

• Phase II: Patients are randomized to 1 of 3 treatment arms.

  • Arm I: Patients receive gemtuzumab ozogamicin (GO) IV over 2 hours on days 1 and 8. Patients with stable or responding disease at day 36 receive GO IV over 2 hours every 4 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity.
  • Arm II: Patients receive GO IV over 2 hours on days 1, 3, and 5. Patients with stable or responding disease at day 36 receive GO IV over 2 hours every 4 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity.
  • Arm III: Patients receive standard supportive care.

• Phase III: Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive the selected treatment (arm I or arm II) from phase II.
  • Arm II: Patients receive standard supportive care. Patients who receive GO treatment are followed monthly for 1 year and then every 3 months thereafter. Patients who receive standard supportive care are followed at least every 4 weeks.

PROJECTED ACCRUAL: A total of 259 patients (75 for phase II [25 per treatment arm] and 184 for phase III [92 per treatment arm]) will be accrued for this study within 2.5 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed acute myeloid leukemia (AML)

  • At least 20% bone marrow blasts by bone marrow aspiration or biopsy
  • All subtypes except M3 (acute promyelocytic leukemia) are allowed

• Previously untreated primary or secondary disease (including AML after myelodysplastic syndromes)

• Ineligible for intensive chemotherapy, as defined by 1 of the following criteria:

  • 61 to 75 years old AND WHO performance status > 2 AND/OR unwilling to receive intensive chemotherapy
  • Over 75 years old

• No blast crisis of chronic myeloid leukemia

• No AML supervention after other myeloproliferative disease

• WBC < 30,000/mm^3 and meets 1 of the following criteria:

  • WBC < 30,000/mm^3 at diagnosis AND had no prior treatment with hydroxyurea
  • WBC ≥ 30,000/mm^3 at diagnosis AND received mandatory pretreatment with hydroxyurea (up to 14 days duration) until WBC < 30,000/mm^3

• No active CNS leukemia

PATIENT CHARACTERISTICS:

Age

• See Disease Characteristics
• 61 and over

Performance status

• See Disease Characteristics

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• No arrhythmia requiring chronic treatment
• No congestive heart failure
• No symptomatic ischemic heart disease
• No other severe cardiovascular disease

Pulmonary

• No severe pulmonary dysfunction ≥ grade 3

Other

• No alcohol abuse
• No severe neurological or psychiatric disease
• No active uncontrolled infection or severe systemic infection
• No other malignancy
• No psychological, familial, sociological, or geographical condition that would preclude study compliance and follow-up
• HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF)
• No concurrent antiangiogenic drugs

Chemotherapy

• See Disease Characteristics
• Concurrent low-dose cytostatic agents (i.e., thioguanine or mercaptopurine) allowed for palliative care (standard supportive care arm only)

Endocrine therapy

• Prior corticosteroids (duration ≤ 14 days ) for primary or secondary AML allowed

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No other concurrent cytotoxic drugs
• No other concurrent experimental therapy
• No concurrent tyrosine kinase inhibitors