COHORTS:
Cohort 1 (Initial cohort: Relapsed AML with previous remission ≥ 3 months), Cohort 2
(Poor-risk cohort: MDS transformed to AML), Cohort 3 (Poor-risk cohort: Refractory or
relapsed AML with previous remission < 6 months)
OBJECTIVES:
- To test whether the complete remission (CR) rate (including CR with incomplete recovery)
in patients with relapsed acute myeloid leukemia (AML) treated with idarubicin and
cytarabine in combination with pravastatin is sufficiently high to warrant a phase III
investigation.
- To estimate relapse-free survival and overall survival rates in these patients.
- To estimate the frequency and severity of toxicities of this regimen in these patients.
- To evaluate, in a preliminary manner, whether pre-study cytogenetic features correlate
with response in these patients.
OUTLINE: This is a multicenter study.
- Induction therapy: Patients receive oral pravastatin once daily on days 1-8, idarubicin
IV over 10-15 minutes on days 4-6, and cytarabine IV continuously on days 4-7. Patients
achieving complete remission proceed to consolidation therapy.
- Consolidation therapy: Beginning 30-60 days after the start of induction therapy,
patients receive oral pravastatin once daily on days 1-6 and idarubicin IV over 10-15
minutes and cytarabine IV continuously on days 4 and 5. Treatment repeats approximately
every 5 weeks for up to 2 courses in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed periodically for 5 years.
Cohort 1 (Initial cohort: Relapsed AML with previous remission >/= 3 months) is permanently
closed to accrual DISEASE CHARACTERISTICS
- Patients must have a previous morphologically confirmed diagnosis of acute myeloid
leukemia (AML). Note: This protocol uses the World Health Organization (WHO)
diagnostic criteria for acute myeloid leukemia (AML) (see Section 4.1). Patients with
acute promyelocytic leukemia (APL, FAB, M3) or blastic transformation of chronic
myelogenous leukemia (CMML) are not eligible.
- Patients must have received at least one prior chemotherapy regimen for their acute
myeloid leukemia (AML) and they may have received any type of chemotherapy. They must
have achieved complete remission (CR), lasting at least three months with their last
induction regimen and they must have relapsed after the last regimen. Relapse must be
documented by a bone marrow examination demonstrating > 5% blasts in the bone marrow
not attributable to another cause. Refractory patients and patients who have received
autologous or allogeneic stem cell transplantation are not eligible. Administration of
hydroxyurea to control high white blood cell (WBC) count prior to, during and after
registration is permitted.
- Patients must not have symptomatic congestive heart failure, coronary artery disease,
cardiomyopathy, or uncontrolled arrhythmias. Either an echocardiogram or
multiple-gated acquisition (MUGA) scan with an ejection fraction ≥ 45% must be
obtained within 28 days prior to registration. (Either method for measuring cardiac
function is acceptable, however, the same scan must be used throughout treatment and
follow-up to monitor the patient for cardiac toxicity.) If patient has symptoms
suggestive of ischemia or congestive heart failure after that cardiac evaluation was
done, a repeat study must be obtained prior to registration.
- Patients must have a serum creatinine < 2.0 mg/dl within 14 days prior to
registration.
- Patients must have a total bilirubin ≤ 2.0 x Institutional Upper Limit of Normal
(IULN) within 14 days prior to registration, unless the elevation is due primarily to
elevated unconjugated hyperbilirubinemia secondary to Gilbert's syndrome or hemolysis
and not to liver dysfunction.
- Patients must have SGOT (AST) ≤ 3.0 x IULN and SGPT (ALT) ≤ 3.0 x IULN within 14 days
prior to registration. Treatment may begin with SGOT/SGPT above those limits, if the
abnormalities are thought to be due to the patient's leukemia.
- Patients must have Zubrod performance status of 0-2 (see Section 10.8).
- Patients must be ≥ 18 years of age.
- Patients must not have clinical evidence of leptomeningeal disease (a spinal tap does
not need to be performed).
- Patients not known to be HIV+ must be tested for HIV infection (the human
immunodeficiency virus) within 14 days prior to registration (see Section 2.0 for
justification). Patients who are HIV+ may be eligible providing they meet all of the
following additional criteria within 14 days prior to registration:
1. Patient must have no history of AIDS defining events.
2. CD4 cells ≥ 500/mm3.
3. Viral load of < 50 copies HIV mRNA/mm3 if on cART or < 25,000 copies HIV mRNA if
not on cART.
4. No zidovudine or stavudine as part of cART. Patients who are HIV+ and do not meet
all of these criteria will not be eligible for this study.
- Patients with prior malignancy (other than AML) are eligible. However, the patient
must be in remission from the prior malignancy and have completed all chemotherapy and
radiotherapy at least 6 months prior to registration and all treatment related
toxicities must have been resolved. NOTE: For patients with prior history of
malignancy who have received anthracyclines or mediastinal/pericardial radiation in
the past, the risk versus benefit of therapy should be weighed, particularly in the
setting of receiving consolidation therapy.
- Patients must not have a systemic fungal, bacterial, viral or other infection that is
not controlled (defined as exhibiting ongoing signs/symptoms related to the infection
and without improvement, despite appropriate antibiotics or other treatment).
- Southwest Oncology Group patients must be registered on SWOG-9007 ("Cytogenetic
Studies in Leukemia Patients"). Collection of pretreatment marrow specimens must be
completed within 28 days prior to registration. Pretreatment specimens of bone marrow
(or peripheral blood if the marrow aspirate is a dry tap) must be submitted to an
approved Southwest Oncology Group Cytogenetics Laboratory for cytogenetics analysis.
Note that protocol SWOG-9007 also requires submission of specimens at additional
timepoints.
- Southwest Oncology Group patients must be offered participation in S9910 ("Leukemia
Centralized Reference Laboratories and Tissue Repositories Ancillary"). If consent is
given, collection of pretreatment blood and/or marrow specimens must be completed
within 28 days prior to registration. If the patient consents to participate in S9910,
pretreatment specimens of marrow and/or peripheral blood must be submitted to the
Southwest Oncology Group Myeloid Repository at the University of New Mexico for
cellular and molecular studies. Note that protocol S9910 also requests submission of
specimens at additional timepoints.
- Women of reproductive potential must have a negative pregnancy test within 14 days
prior to registration. Patients must not be pregnant or nursing because of the
teratogenic potential of the drugs used in this study. Women/men of reproductive
potential must have agreed to use an effective contraceptive method.
- All patients must be informed of the investigational nature of this study and must
sign and give written informed consent in accordance with institutional and federal
guidelines.
- At the time of patient registration, the treating institution's name and ID number
must be provided to the Data Operations Center in Seattle in order to ensure that the
current (within 365 days) date of institutional review board approval for this study
has been entered into the data base.
Cohort 2 (MDS transformed to AML) is permanently closed to accrual AND Cohort 3
(relapsed/refractory AML) is permanently closed to accrual
DISEASE CHARACTERISTICS:
- For patients registered to relapsed/refractory (Cohort 3), morphologically confirmed
diagnosis of acute myeloid leukemia (AML)
- Patient registered to the myelodysplastic syndrome (MDS) transformed to acute myeloid
leukemia (AML) cohort (Cohort 2) patients must have a previous morphologically
confirmed diagnosis of myelodysplastic syndrome/chronic myelomonocytic leukemia
(MDS/CMML). Patients may have received previous non-intensive therapy (such as:
azacitidine, decitabine, low-dose cytarabine, lenalidomide) given treatment of
myelodysplastic syndrome/chronic myelomonocytic leukemia (MDS/CMML) (with up to 20%
blasts). At time of registration, patient must have morphologically confirmed
diagnosis of acute myeloid leukemia (AML).
- Patients with acute promyelocytic leukemia (i.e., APL, FAB M3) or blastic
transformation of chronic myelogenous leukemia are not eligible
- Patients must not have received autologous or allogeneic stem cell transplant.
- Patients in the relapsed/refractory acute myeloid leukemia (AML) cohort (Cohort 3)
must:
- Have received ≥ 1 prior chemotherapy regimen for acute myeloid leukemia (AML)
- Any type of prior chemotherapy allowed
- Administration of hydroxyurea to control high white blood cell (WBC) prior
to, during, and after registration is permitted
- Relapse must be documented by a bone marrow examination demonstrating > 5% blasts
in the bone marrow not attributable to another cause
- Patient must not have received chemo within 14 days prior to registration
- Primary refractory patients eligible if, on Day 14 of previous chemo regimen, they
have significant residual disease. Patients who received only hypomethylating agent or
low dose therapy for Induction are not considered primary refractory for this study
and are not eligible.
- Relapsed patients must have achieved a complete remission (CR) or CR with incomplete
blood count recovery that lasted < 6 months after the last induction regimen
- No clinical evidence of leptomeningeal disease
- Pretreatment (collected within 28 days of registration) cytogenetics must be performed
on all patients.
- Patients must have complete history and physical exam within 28 days prior to
registration.
PATIENT CHARACTERISTICS:
- No symptomatic congestive heart failure, coronary artery disease, cardiomyopathy, or
uncontrolled arrhythmias
- Ejection fraction ≥ 45% by echocardiogram or MUGA scan within 28 days prior to
registration (or within 14 days prior to registration if the patient has received
anthracycline in the 28 day window)
- Zubrod performance status 0-2
- Serum creatinine ≤ 2.0 times upper limit of normal (ULN)
- Total bilirubin ≤ 2.0 times ULN (unless elevation is primarily due to elevated
unconjugated hyperbilirubinemia secondary to Gilbert's syndrome or hemolysis AND not
due to liver dysfunction)
- AST and ALT ≤ 3.0 times ULN
- Not pregnant or nursing and negative pregnancy test within 14 days prior to
registration. Females of child-bearing potential must agree to use effective
contraception
- No HIV positivity unless the following criteria are met:
- No history of AIDS-defining events
- CD4 count ≥ 500/mm³
- Viral load < 25,000 copies (< 50 copies if on combination antiretroviral therapy)
- Not receiving zidovudine or stavudine as part of combination antiretroviral
therapy
- No uncontrolled systemic fungal, bacterial, viral, or other infection, defined as
exhibiting ongoing signs/symptoms related to the infection with no improvement despite
appropriate antibiotics or other treatment
- Patients with prior malignancy (other than AML and MDS/CMML) eligible provided patient
is in remission from that malignancy at least 6 months prior to registration. Except
for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) treatment, all
treatment related toxicities must have been resolved.
