Clofarabine or Daunorubicin Hydrochloride and Cytarabine Followed By Decitabine or Observation in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia

Phase III Randomized Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard Daunorubicin &Amp; Cytarabine Induction and Intermediate Dose Cytarabine Post-Remission Therapy, Followed by Decitabine Maintenance vs. Observation in Newly-Diagnosed Acute Myeloid Leukemia in Older Adults (Age >/= 60 Years)

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.

PRIMARY OBJECTIVES:

I. To evaluate the effect of clofarabine induction and consolidation therapy on overall survival in comparison with standard therapy (daunorubicin [daunorubicin hydrochloride] & cytarabine) in newly-diagnosed acute myeloid leukemia (AML) patients age >= 60 years.

SECONDARY OBJECTIVES:

I. To evaluate complete remission (CR) rates, duration of remission, and toxicity/treatment-related mortality of clofarabine in comparison with standard therapy (daunorubicin & cytarabine) in newly-diagnosed AML patients age >= 60 years.

II. To evaluate the feasibility of consolidation with reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation from human leukocyte antigen (HLA)-identical donors in patients who achieve a response to induction therapy, including the incidence of successful engraftment, acute and chronic graft-versus-host disease, transplant-related mortality, and its impact on overall survival in comparison to patients receiving chemotherapy.

III. To evaluate the duration of remission and disease-free survival of patients in complete remission following completion of consolidation therapy who are subsequently randomized to receive scheduled low-dose decitabine maintenance in comparison with observation.

IV. To perform expression and methylation profiling on all patients receiving decitabine and to correlate their integrated epigenetic signatures with response to decitabine.

V. To examine the epigenetic profiles of remission marrow in patients randomized to observation vs. decitabine to determine whether epigenetic signature of apparently morphologically normal bone marrow is predictive of relapse or response to decitabine maintenance.

VI. To explore the possible association of response to clofarabine with ABC-transporter P-glycoprotein (Pgp).

VII. To assess the intensity of expression of CXC chemokine receptor type 4 (CXCR4) on diagnostic leukemia cells and to correlate this parameter with other established prognostic factors.

VIII. To assess the entire spectrum of somatic mutations and affected pathways at diagnosis of AML and elucidate the association between gene mutation and outcome.

IX. To examine the impact of smoking, obesity, regular acetaminophen use, regular aspirin use, benzene exposure, living in a rural/farm environment and some other underlying exposures and lifestyle factors associated with AML development on overall survival (OS).

X. To investigate potential correlative results between array comparative genomic hybridization (CGH) findings and acute myeloid leukemia patient characteristics.

TERTIARY OBJECTIVES:

I. To compare health-related quality of life (QOL) (physical, functional, leukemia-specific well-being) and fatigue in elderly AML patients receiving standard induction therapy with those receiving clofarabine.

II. To measure the change in health-related QOL that occurs over time (within treatment groups).

III. To comprehensively assess patient function at the time of study enrollment.

IV. To determine if components of a comprehensive geriatric assessment or QOL scales predict ability to complete AML treatment.

V. To describe the impact of transplant on QOL in AML patients above age 60.

OUTLINE:

INDUCTION THERAPY: Patients are randomized to 1 of 2 treatment arms.

ARM A (STANDARD THERAPY): Patients receive daunorubicin hydrochloride at 60 mg/m^2 intravenously (IV) over 10-15 minutes on days 1-3 and cytarabine at 100 mg/m^2 IV continuously on days 1-7. Patients with residual disease or those who do not achieve an aplastic bone marrow on day 12-14 (i.e., < 5% blasts and < 20% cellularity or markedly/moderately hypocellular) may receive a second course of induction therapy beginning no sooner than day 14.

ARM B: Patients receive clofarabine at 30 mg/m^2 IV over 1 hour on days 1-5. Patients with residual disease or those who do not achieve an aplastic bone marrow on day 12-14 (i.e., < 5% blasts and < 20% cellularity or markedly/moderately hypocellular) may receive a second course of induction therapy beginning no sooner than day 21 and no later than day 56.

Patients who achieve a complete remission (CR) or CR with incomplete marrow recovery (CRi) after induction therapy proceed to consolidation therapy (Arms C and D). Patients who are 60-69 years of age who achieve a "morphologic leukemia-free state" after induction therapy and who have an HLA-identical donor proceed to allogeneic stem cell transplantation.

CONSOLIDATION THERAPY: Beginning within 60 days after documentation of CR or CRi, patients receive consolidation therapy in the same arm they were randomized to for induction therapy.

ARM C (STANDARD THERAPY): Patients receive cytarabine at 1500 mg/m^2 IV over 1 hour once or twice daily on days 1-6. Treatment repeats every 4-6 weeks for 2 courses.

ARM D: Patients receive clofarabine at 20 mg/m^2 IV over 1 hour on days 1-5. Treatment repeats every 4-6 weeks for 2 courses.

Patients who remain in CR after completion of consolidation therapy are randomized to one of the two maintenance therapy arms (Arms E and F).

MAINTENANCE THERAPY: Beginning within 60 days after completion of consolidation therapy, patients receive maintenance therapy and are randomized to 1 of 2 arms. Patients not eligible for randomization to decitabine maintenance after recovery from consolidation will be followed according to Arm E.

ARM E: Patients undergo observation monthly for 12 months.

ARM F: Patients receive decitabine at 20 mg/m^2 IV over 1 hour on days 1-3. Treatment repeats every 4 weeks for 12 months the absence of unacceptable toxicity.

ALLOGENEIC STEM CELL TRANSPLANTATION WITH REDUCED-INTENSITY CONDITIONING REGIMEN (Arm G): Patients begin reduced-intensity conditioning 30-90 days after the initiation of induction therapy.

CONDITIONING REGIMEN: Patients receive fludarabine phosphate at 30 mg/m^2 IV over 30 minutes on days -7 to -3, busulfan at 0.8 mg/kg IV over 2 hours every 6 hours on days -4 and -3 (for a total of 8 doses), and anti-thymocyte globulin at 2.5 mg/kg/day IV over 4-6 hours on days -4 to -2.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.

After completion of study treatment, patients are followed up every 3 months for 4 years, every 6 months for 1 year, and then annually thereafter.

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