Low Dose Daunorubicin in Pediatric Relapsed/Refractory Acute Leukemia
Condition: Relapsed Pediatric ALL; Relapsed Pediatric AML; Refractory Acute Myeloid Leukemia; Refractory Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma
Study type: Interventional
Phase: Phase 2

Summary: 
      In this pilot study, eligible pediatric patients will be treated with 5 consecutive days of
      low dose daunorubicin. All patients who receive low dose daunorubicin will be evaluated daily
      for potential toxicity during those 5 days. Once the patient has received 5 doses of
      daunorubicin, subsequent therapy will be at the discretion of the primary oncology team.
    

Detailed description: 
      Cancer remains the number one cause of non-accidental death in children with leukemia being
      the most common type of childhood cancer. Although cure rates for pediatric leukemia have
      greatly improved over the last few years, relapsed disease still carries a poor prognosis.
      Outcomes for children with multiply relapsed leukemia are dismal ranging from a remission
      rate of 25% in AML after 2 relapses falling to 17% after 3 or more relapses and 44% in ALL
      after 2 relapses and 27% after 3 or more relapses.

      Leukemia stem cells that are resistant to chemotherapy primarily contribute to treatment
      failure and targeting these cells remains a challenge. Anthracyclines such as daunorubicin
      and doxorubicin have been the mainstays of childhood leukemia therapy for over 50 years.
      Prior investigations found that very low doses, significantly less than traditionally given,
      of doxorubicin and daunorubicin inhibit the interaction of Akt and beta catenin pathways
      which is known to drive the development of leukemia stem cells and chemoresistance. Mice
      models showed that treatment with these very low dose anthracyclines does not suppress the
      immune system but rather expands cancer targeting T cells while inhibiting populations known
      to help cancer cells evade the immune system. In addition, targeted treatment reduced immune
      checkpoint expression, a known cause of resistance, on leukemia stem cells, thus further
      sensitizing them to cytotoxic T cells. Standard doses of anthracyclines suppress
      hematopoiesis and in turn the immune system and thus do not permit the expression of these
      immunologic benefits.

      Patients with relapsed and/or refractory acute lymphoblastic leukemia or acute myeloid
      leukemia, ages 1-21 years, will be approached to participate in this study. These patients
      must have pathologically confirmed ALL or AML, whose disease is refractory to two induction
      therapeutic attempts, or who are in 2nd or greater relapse, or who are in 1st relapse or
      refractory to a single therapeutic attempt but are unable to receive intensive therapy due to
      other comorbidities. Patients will receive daunorubicin at 6.75mg/m2 daily for 5 consecutive
      days for a total dose of 33.75mg/m2.

      The primary objective of this study is to assess the feasibility and tolerability of low dose
      daunorubicin. Another objective of the study is to validate if T cell based immune responses
      against chemoresistant leukemia stem cells are stimulated at these lower doses of
      daunorubicin, in hopes to provide preliminary pediatric data for further research with the
      hypothesis being that targeted anthracycline treatment does in fact stimulate T cell based
      immune responses against chemoresistant leukemia stem cells. Samples will be analyzed by flow
      cytometry for stem cell and immune markers. The third primary objective is to identify pro vs
      anti-cancer cellular immune responses of targeted anthracycline treatment in these patients.
      The mechanism of low dose DNR treatment on activating immunogenic cell death (ICD) will be
      investigated by determining relative levels of damage-associated molecular patterns. The
      tumorigenic capacity of resistant populations such as LSCs expressing high levels of immune
      checkpoints will be tested. The secondary objective of this study is to evaluate the
      pharmacokinetic parameters of low dose daunorubicin in children with relapsed/refractory AML
      and ALL. Blood samples for evaluation of low dose daunorubicin pharmacokinetics (area under
      the time concentration curve, maximum concentration, elimination half-life, clearance) will
      be drawn prior to dosing and 5min, 20min, 40min, 1hr, 2hrs, 4hrs, 8hrs, and 24hrs only after
      the first day of dosing.

      Once the patient has received 5 doses of daunorubicin, subsequent therapy will be at the
      discretion of the primary oncology team.
    

Intervention name(s): Daunorubicin
Intervention type(s): Drug
Intervention description(s): Eligible patients with relapsed and/or refractory acute leukemia will receive daunorubicin 6.75mg/m2 daily for 5 consecutive days.
Intervention MeSH terms: Daunorubicin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment