Biomarkers for Personalized Early Assessment of Response During Salvage Chemotherapy in People With Relapsed or Refractory Acute Myeloid Leukemia (PEARL15)

Effective treatment of patients with relapsed and refractory acute myeloid leukemia (RR-AML)
remains a significant unmet need. Current response criteria were originally proposed in 1956
and do not provide a sensitive assessment of AML disease burden, as evidenced by the
disconnect between the apparent success of current induction therapy in achieving complete
remission in most patients and the stark reality of median overall survival times of less
than two years. While sensitive minimal/measurable residual disease assays assessing AML
disease burden have been developed, the role for these tests in the treatment algorithm for
patients with RR-AML has yet to be defined. We propose evaluating if these high sensitivity
assays could function as early predictors of salvage therapy failure.

This protocol is designed as a feasibility study to evaluate if use of high sensitivity
peripheral blood-based molecular assays on day 4 of induction salvage chemotherapy can
predict failure to ultimately achieve a CR or CRi in patients with RR-AML. Eligible patients
will receive salvage induction therapy using FDA approved antineoplastic agents given either
alone or in combinations as defined in the National Comprehensive Cancer Network (NCCN)
Clinical Practice Guidelines in Oncology for AML.

Additional secondary objectives include investigating the relationship between kinetics of
gene expression changes and response to chemotherapy, determining the proportion of patients
for whom results of day 4 peripheral blood gene expression testing are available before day 8
of therapy, determining the proportion of patients for whom results from pre-treatment
molecular and genetic testing are available before day 8 of therapy, assessing patient and
disease specific factors associated with failure to achieve a CR, determining the feasibility
of measuring AML residual disease burden using alternative technologies and alternative
tissue sources, determining the proportion of patients who receive allogeneic hematopoietic
stem cell transplant after completion of therapy, determining the incidence of infectious
complications with the use of modern prophylactic antimicrobial agents compared with
historical comparisons and determining the feasibility of recruiting patients with RR-AML to
the NIH Clinical Center.

- INCLUSION CRITERIA:

- Unequivocal diagnosis of relapsed or refractory acute myeloid leukemia (AML) according
to WHO criteria confirmed by bone marrow evaluation within 30 days prior to study
enrollment

- Age 18-70 years inclusive

- ECOG performance status of 0 to 2

- Must have received at least one prior AML therapy before study enrollment

- Ability to comprehend the investigational nature of the study and provide informed
consent

- Availability of a physician willing to assume clinical care after completion of this
research study.

- Subject agreement to use a medically-approved method of contraception to avoid
pregnancy throughout the study if a woman of childbearing potential or a male subject
with partner of childbearing potential.

EXCLUSION CRITERIA:

- Diagnosis of acute promyelocytic leukemia

- Decreased oxygen saturation at rest (e.g. pulse oximeter less than 88% or PaO2 less
than or equal to 55 millimeters of mercury)

- Clinically significant active infection not responding adequately to therapy

- Known positive or history of HIV; active Hepatitis B or C infection. If unknown,
screening will be done but results are not needed before proceeding with treatment

- Prior allogeneic hematopoietic stem cell transplant

- Additional malignancy requiring concurrent treatment

- Uncontrolled hepatic, renal, cardiac, gastrointestinal, pulmonary, neurologic,
infectious, metabolic or other disease of such severity, which in the opinion of the
PI, would preclude ability to tolerate protocol.

- Severe psychiatric illness or complex social situations that would limit the patient s
ability to tolerate and/or comply with study requirements.

- Active central nervous system (CNS) leukemic infiltration

- Current pregnancy or breastfeeding

- Prolonged QTc interval prior to therapy (>470ms)