Comparing Three Different Combination Chemotherapy Regimens in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

• Achievement of CR+CRc+CRi [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  The confidence interval for the observed response rate will be calculated by the Atkinson and Brown procedure.
  
  
• Incidence and severity of toxicity of each induction/consolidation regimen as assessed by NCI CTCAE v4.0 [ Time Frame: At each course to up to 3 years ] [ Designated as safety issue: Yes ]
  Treatment-related toxicities will be monitored closely for each treatment arm. Toxicity will be monitored using ECOG's standard adverse event (AE) mechanism.
  
  

• Rate of treatment failure [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

  The definition of treatment failure will include:

  • >= 5% leukemic blasts at the time of pre-consolidation marrow
  • Death during/following induction chemotherapy (pre-consolidation)
  • Persisting marrow hypoplasia and pancytopenia for >= 2 months after chemotherapy
  • CNS or extramedullary disease at the time of pre-consolidation
  • Leukemia persistence after completion of induction treatment; leukemia persistence is defined as greater than 10% residual blasts on marrow biopsy done 5-7 days after completion of induction chemotherapy
  
  

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.