Clofarabine or Daunorubicin Hydrochloride and Cytarabine Followed By Decitabine or Observation in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia
Condition: Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Myelodysplastic Syndromes
Intervention: Daunorubicin; Cytarabine; Clofarabine; Decitabine; Observation; Allogeneic hematopoietic stem cell transplantation
Intervention description: Given IV; Given IV; Given IV; Given IV; Undergo clinical observation; Patients with an HLA-identical donor proceed to allogeneic stem cell transplantation.
Intervention MeSH terms: Cytarabine; Decitabine; Clofarabine; Azacitidine; Daunorubicin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 727.0
Sex: All
Minimum age: 60 Years
Healthy volunteers: No
Keywords: acute myeloid leukemia; Clofarabine; Daunorubicin; Cytarabine; Decitabine

Summary:

      This randomized phase III trial studies clofarabine to see how well it works compared with
      daunorubicin hydrochloride and cytarabine when followed by decitabine or observation in
      treating older patients with newly diagnosed acute myeloid leukemia. Drugs used in
      chemotherapy, such as clofarabine, daunorubicin hydrochloride, cytarabine, and decitabine,
      work in different ways to stop the growth of cancer cells, either by killing the cells or by
      stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill
      more cancer cells. It is not yet known which chemotherapy regimen is more effective in
      treating acute myeloid leukemia.
    

Eligibility criteria:

        Inclusion Criteria for Step 1 (Induction):

          -  Sexually active males must be strongly advised to use an accepted and effective method
             of contraception

          -  Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin =<
             grade 1

          -  Newly-diagnosed AML patients according to World Health Organization (WHO)
             classification who are considered candidates for intensive chemotherapy based upon
             examination of peripheral blood or bone marrow aspirate specimens or touch
             preparations of the bone marrow biopsy obtained within two weeks prior to
             randomization; a bone marrow aspirate is required for enrollment; however, on occasion
             there is discordance between percentage of myeloblasts on the differential of the
             peripheral blood or aspirate; the peripheral blood criteria are sufficient for
             diagnosis; confirmatory immunophenotyping will be performed centrally

          -  ECOG performance status (PS) 0-3 (restricted to ECOG PS 0-2 if >= 70 years of age)

          -  Patients with secondary AML are eligible for enrollment onto the trial; secondary AML
             is defined as AML that has developed in a person with a history of antecedent blood
             count abnormalities, or myelodysplastic syndrome (MDS), or a myeloproliferative
             disorder (excluding chronic myeloid leukemia); or a history of prior chemotherapy or
             radiation therapy for a disease other than AML

          -  Total serum bilirubin =< 1.5 times upper limit of normal (ULN) (=< grade 1); if total
             bilirubin is 2 to 3 mg/dL, but direct bilirubin is normal, then the patient will be
             considered eligible

          -  Patients with a serum creatinine > 1 are eligible if they have a calculated glomerular
             filtration rate (GFR) of >= 60 ml/min (i.e. class I or class II chronic kidney disease
             ) using the Modification of Diet in Renal Disease (MDRD) formula

               -  Note: Daily creatinine and MDRD formula are only for the 1st induction cycle

          -  Cardiac ejection fraction >= 45% or within institutional normal limits; a nuclear
             medicine gated blood pool examination is preferred; a two-dimensional (2-D)
             echocardiogram (ECHO) scan is acceptable if a calculated ejection fraction is obtained
             and follow-up measurement of the cardiac ejection fraction will also be performed by
             echocardiography; measurement of cardiac ejection fraction should be within two weeks
             prior to receiving treatment

               -  NOTE: when a multi gated acquisition scan (MUGA) or echocardiogram cannot be
                  obtained due to weekend or holiday, then patients may be enrolled provided there
                  is no history of significant cardiovascular disease and a measurement of cardiac
                  ejection fraction will be performed within 5 days of study enrollment

          -  Patients with suspected central nervous system (CNS) involvement should undergo lumbar
             puncture

          -  Cytogenetic analysis must be performed from diagnostic bone marrow (preferred) or if
             adequate number of circulating blasts (>10^9/l) from peripheral blood

          -  HLA typing should be performed at registration, if possible

          -  Diagnostic bone marrow and peripheral blood specimens must be submitted for
             immunophenotyping and selected molecular testing

        Exclusion Criteria for Step 1 (Induction):

          -  Concurrent active malignancy for which they are receiving treatment (other than
             myelodysplastic syndromes [MDS])

          -  Active, uncontrolled infection

          -  Acute promyelocytic leukemia (APL) confirmed either by the presence of
             t(15;17)(q22;q21) or promyelocytic leukemia (PML)/retinoic acid receptor (RAR) alpha
             transcripts

          -  Blastic transformation of chronic myelogenous leukemia

          -  Prior therapy of MDS with decitabine, low-dose cytarabine, or azacitidine

          -  Prior chemotherapy for AML with the exception of hydroxyurea for increased blast count
             or leukapheresis for leukocytosis

          -  Documented CNS involvement

          -  Previous treatment for antecedent hematological disorders (AHD) with 5-azacitidine,
             decitabine, or low dose cytarabine

          -  Human immunodeficiency virus (HIV) infection

        Inclusion Criteria for Step 2 (Consolidation)

          -  NOTE: All patients achieving complete remission (CR) or complete remission with
             incomplete blood count recovery (CRi) will receive consolidation when fit

          -  NOTE: Patients proceeding to transplant are allowed up to one cycle of consolidation
             treatment

          -  Consolidation cycle 1 must commence within sixty days of the bone marrow aspirate and
             biopsy that confirmed the presence of a CR or CRi

          -  Patients must have achieved a CR or CRi (or morphologic leukemia-free state for those
             patients proceeding to Arm G transplant)

          -  Patients who have achieved a CR or CRi must have maintained peripheral blood evidence
             of a CR or CRi

          -  ECOG performance status of 0-2

          -  Patients must have resolved any serious infectious complications related to induction

               -  NOTE: Patients with an HLA-matched donor and proceeding to transplant will be
                  allowed up to one cycle of consolidation treatment

          -  Any significant medical complications related to induction must have resolved

          -  Patients must have a creatinine and AST =< grade 1 within 48 hours prior to
             registration

        Inclusion Criteria for Step 3 (Maintenance):

          -  Maintenance should commence within 60 days of recovery of peripheral blood counts
             after consolidation cycle 2; patients must begin consolidation cycle 2 within 60 days
             of recovery to be eligible for further therapy

          -  Patients must have maintained peripheral blood evidence of a remission and must have a
             CR or CRi, confirmed on restaging bone marrow (BM) aspirate and biopsy and cytogenetic
             analysis

          -  ECOG performance status of 0 -2

          -  Patients must have resolved any serious infectious complications related to
             consolidation cycle 2

          -  Any significant medical complications related to consolidation cycle 2 must have
             resolved

          -  Total serum bilirubin =< 1.5 x ULN

               -  NOTE: if total bilirubin is 2-3 mg/dL, but direct bilirubin is normal, then the
                  patient will be considered eligible

          -  Serum creatinine =< grade 1

          -  The absolute neutrophil count (ANC) must be > 1000 mm^3 prior to starting every cycle
             of treatment with decitabine; decitabine may be delayed for up to 4 weeks between
             cycles (i.e. may be administered as infrequently as every (q) 8 weeks) while waiting
             for counts to recover

          -  The platelet count must be > 75,000 mm^3 prior to starting every cycle of treatment
             with decitabine; decitabine may be delayed for up to 4 weeks between cycles (i.e. may
             be administered as infrequently as every (q) 8 weeks) while waiting for counts to
             recover

        Inclusion Criteria for Step 3 (Allogeneic Transplantation):

          -  Patients must be > 28 days from the start of induction or re-induction chemotherapy,
             or from the start Consolidation Cycle 1 (if received) and < 90 days following recovery
             from most recent treatment; and they must have achieved and maintained a response to
             induction therapy (CR, CRi, or "morphologic disease-free state")

          -  Patients must have recovered from the effects of induction, re-induction, or
             consolidation chemotherapy (all toxicities =< grade I with the exception of reversible
             electrolyte abnormalities), and have no ongoing active infection requiring treatment

          -  Patients must have a total serum bilirubin =< 1.5 x ULN (grade =< 1) and a serum
             creatinine =< grade 1; AST <= grade 1

          -  An eligible HLA-identical donor (either related or unrelated) should be available; in
             sibling donors, low resolution HLA typing (A,B,DR) will be considered sufficient; in
             the case of unrelated donors, high-resolution class I and II typing (A, B, C, DRB1 and
             DQ) should be matched at all 10 loci; donors must be willing and able to undergo
             peripheral blood progenitor mobilization

               -  HLA-identical sibling (6/6): the donor must be determined to be an HLA-identical
                  sibling (6/6) by serologic typing for class (A, B) and low resolution molecular
                  typing for class II (DRB1)

               -  Matched unrelated donor (10/10): high resolution molecular typing at the
                  following loci is required: HLA-A, -B, -C, -DRBL, and -DQB1

               -  NOTE: for matched donors - will allow select 1 antigen mismatched sibling donors
                  and unrelated donors in accordance with site institutional standard, as long as
                  matched at HLA-A, HLA-B, HLA-C, and DRB1, and with advanced discussion/approval
                  by the Study Chair and the bone marrow transplant (BMT) co-chair

          -  Patients must be considered reliable enough to comply with the medication regimen and
             follow-up, and have social support necessary to allow this compliance

          -  Patients must have a cardiac ejection fraction of >= 40%, or within institutional
             normal limits; a nuclear medicine gated blood pool examination is preferred; a 2-D
             ECHO scan is acceptable if a calculated ejection fraction is obtained and follow-up
             measurement of the cardiac ejection fraction will also be performed by
             echocardiography; measurement of cardiac ejection fraction should be within two weeks
             prior to allogeneic transplantation

          -  Diffusion capacity of carbon monoxide (DLCO) > 40% with no symptomatic pulmonary
             disease

        Exclusion Criteria for Step 3 (Allogeneic Transplantation):

          -  Hypersensitivity to Escherichia (E.) coli-derived products

          -  Human immunodeficiency virus (HIV) infection; patients with immune dysfunction are at
             a significantly higher risk of toxicities from intensive immunosuppressive therapies