Clinical Trials

PRIMARY OBJECTIVES:

     I. To determine the CR + CRc + CRi rate of carboplatin and topotecan; flavopiridol, mitoxantrone and cytosine arabinoside and sirolimus, mitoxantrone, etoposide and cytosine arabinoside in adult patients with refractory or relapsed AML.

     II. To determine the rate of treatment failure of these regimens. III. To determine the incidence and severity of toxicities of these regimens. IV. To analyze the predictive value of blast cell properties that have been suggested to determine response. (Correlative laboratory studies) V. To determine whether pretreatment levels of Bcl-2 or, alternatively, whether a therapy-induced change in topoisomerase I levels correlates with response to this regimen. (Correlative laboratory studies) VI. To assess the impact of clonal evolution by comparing cytogenetic abnormalities at the time of relapse with those at initial diagnosis and correlating these abnormalities and changes with response to the treatment regimens in this protocol. (Cytogenetic and FISH Studies) VII. Panel FISH studies for common AML rearrangements will be performed on relapse AML specimens to determine the presence of these recurrent AML abnormalities and to evaluate for subtle additional abnormalities consistent with clonal evolution in these relapse specimens. (Cytogenetic and FISH Studies)

     OUTLINE: This is a multicenter, randomized study. Patients are stratified according to disease status (relapse ≤ 6 months after achieving first complete remission [CR] vs relapse between 6-12 months after achieving first CR vs refractory to ≤ 2 courses of initial conventional induction chemotherapy vs refractory to ≤ 1 course of first reinduction chemotherapy). Patients are randomized to 1 of 3 treatment arms. Induction therapy:

     ARM I: Patients receive carboplatin and topotecan hydrochloride IV continuously over 24 hours on days 1-5.

     ARM II: Patients receive alvocidib IV over 4.5 hours once daily on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9.

     ARM III: Patients receive oral sirolimus once daily on days 2-9, mitoxantrone hydrochloride IV over 15 minutes once daily, etoposide IV over 1 hour once daily, and cytarabine IV over 3 hours once daily on days 4-8 or 5-9.

     After completion of induction therapy, patients in all arms undergo bone marrow aspirate and biopsy. Patients with persistent leukemia (i.e., leukemic blasts ≥ 10%) are removed from study and are offered alternative therapy at the discretion of the investigator. Patients who achieve CR proceed to consolidation therapy or receive alternative therapy at the discretion of the investigator.

     CONSOLIDATION THERAPY: Beginning within 2-6 weeks after documentation of CR, patients may receive up to 2 additional courses of the same treatment they received during induction therapy. Courses repeat every 4-10 weeks in the absence of disease progression or unacceptable toxicity.

     After completion of study therapy, patients are followed periodically for up to 3 years.

OBJECTIVES:

     Primary

       -  To compare the overall survival of older patients with newly diagnosed acute myeloid leukemia (AML) treated with clofarabine as induction therapy and consolidation therapy vs standard daunorubicin hydrochloride and cytarabine.

     Secondary

       -  To evaluate complete remission (CR) rates, duration of remission, and toxicity/treatment-related mortality of patients treated with these regimens.

       -  To evaluate the feasibility of consolidation therapy with reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation from HLA-identical donors, in terms of the incidence of successful engraftment, acute and chronic graft-vs-host disease, and transplant-related mortality in select patients age 60-69 years who achieve a response to induction therapy.

       -  To determine the impact of reduced-intensity conditioning and allogeneic stem cell transplantation on overall survival of select patients.

       -  To compare the duration of remission and disease-free survival of patients in CR following completion of consolidation therapy who are subsequently randomized to receive decitabine as maintenance therapy vs observation.

       -  To perform expression and methylation profiling in patients treated with decitabine as maintenance therapy and to correlate their integrated epigenetic signatures with response to decitabine.

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

       -  To explore the possible association of response to clofarabine with nucleoside transporters hENT1, hCNT3, and ABC-transporter P-glycoprotein.

       -  To assess the intensity of expression of CXCR4 on diagnostic leukemia cells and to correlate this parameter with other established prognostic factors.

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

     Tertiary

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

       -  To measure the change in health-related QOL that occurs over time.

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

       -  To determine if components of a comprehensive geriatric assessment or QOL scale predict ability to complete treatment for AML.

       -  To describe the impact of transplantation on QOL in patients with AML over 60 years of age.

     OUTLINE: This is a multicenter study. Patients are stratified according to age (60-69 years vs ≥ 70 years), , disease type (secondary vs de novo), therapy-related AML (yes vs no), and antecedent hematologic disorder (yes vs no).

       -  Induction therapy: Patients are randomized to 1 of 2 treatment arms.

            -  Arm I (standard therapy): Patients receive daunorubicin hydrochloride IV over 10-15 minutes on days 1-3 and cytarabine 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 II: Patients receive clofarabine 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 incomplete (CRi) after induction therapy proceed to consolidation therapy. 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. Patients undergoing second induction who do not achieve CR by day 56 of the start of re-induction are taken off protocol.

       -  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 I (standard therapy): Patients receive cytarabine IV over 1 hour once or twice daily on days 1-6. Treatment repeats every 4-6 weeks for 2 courses.

            -  Arm II: Patients receive clofarabine 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 proceed to maintenance therapy.

       -  Maintenance therapy: Beginning within 60 days after completion of consolidation therapy, patients receive maintenance therapy and are randomized to 1 of 2 arms.

            -  Arm I: Patients undergo observation monthly for 12 months.

            -  Arm II: Patients receive decitabine 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: Patients begin reduced-intensity conditioning 30-90 days after the initiation of induction therapy.

            -  Conditioning regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 2 hours every 6 hours on days -4 and -3 (for a total of 8 doses), and anti-thymocyte globulin IV over 4-6 hours on days -4 to -2.

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

     Patients complete quality-of-life questionnaires periodically, including health-related quality of life, physical and functional well-being, and fatigue questionnaires.

     Peripheral blood, bone marrow, and karyotype samples are collected periodically for cytogenetic analysis and other correlative laboratory studies.

     After completion of study treatment, patients are followed up periodically for ≥ 5 years.