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.
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
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.
- Patients with 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 at the time of consent.
- All prior upfront therapies including bone marrow transplant are acceptable. Pulse
steroids (of 5 days duration or less in the prior month) administered as part of a
routine maintenance therapy are acceptable.
- Age 1 to 21 years of age, inclusive
- Established central catheter IV access
- Females who are known to be pregnant or lactating
- Any Grade 3 or higher Cardiac Disorder per CTCAE version 5
- Patients with echocardiographic evidence of cardiomyopathy (shortening fraction <27%
or ejection fraction <50%)
- Uncontrolled sepsis
- Absolute Blast Count >50 x10(3)/mcL at enrollment or on day 1 of study
- Direct hyperbilirubinemia >5mg/dL
- Grade 3 or higher anaphylaxis to daunorubicin
- Non-English speaking
- Patients, who in the opinion of the PI, are unable to tolerate any study-specific
- Patients who have received cyclosporine, tacrolimus or other agents to prevent or
treat graft-vs-host disease post bone marrow transplant in the last 14 days
- Concurrent investigational drugs or other chemotherapeutic agents (excluding
hydroxyurea), immunotherapies or biosimilars during the 5 days of daunorubicin.
- Prior cumulative doses of anthracyclines will not be an exclusion regardless of the
total cumulative dose previously received.