Acute Myeloid Leukemia (AML)

Introduction

Acute myeloid leukemia (AML) is an aggressive, rapidly fatal blood cancer. Treatment modalities exist, but the complete remission rate during induction therapy is only 60-80% in young adults and decreases as patients age or if they suffer from other comorbidities. New treatment modalities are needed to overcome chemoresistance and improve morbidity and mortality. CBD, with growing evidence to support its role in cancer treatment, is a potentially safe and promising adjunctive therapy for the treatment of AML. When used in combination with other therapies, it has the potential to potentiate the effects of the chemotherapy while decreasing toxic side effects to patients.

Preclinical data suggests that the combination of CBD with conventional AML therapy can lead to enhanced anticancer activity through the modification of key signaling pathways. There is also exciting potential for combination therapy of ChEH/AEBS inhibitors with cannabinoids as shown by recent in vitro studies at Soroka University. However, further research and clinical trials are necessary to determine the exact signaling pathways impacted by CBD, the optimal combination of cannabinoids needed to elicit antineoplastic responses, and the ideal sequencing of the cannabinoids and chemotherapy to induce apoptosis of AML cell lines. Further, large scale clinical trials are necessary to achieve these results.

Myeloblasts with Auer rods characteristic of AML.

Image Credit: Paulo Henrique Orlandi Mourao

About Acute Myeloid Leukemia

Leukemias are cancers of cells that would normally develop into different types of blood cells. There are several types of leukemia, which are classified based on their precursor cell line and whether the leukemia is acute (fast growing) or chronic (slower growing). Acute myeloid leukemia (AML) is a cancer syndrome that starts in the bone marrow and moves quickly into the blood. AML often develops from hematopoietic precursor cells. These malignant cells exhibit abnormal growth and differentiation and suppress normal bone marrow activity (Cancer.org).

AML is the most common form of acute leukemia in adults.  The median age at diagnosis is approximately 65 years, and incidence increases with age. In the EU, the incidence rate of AML has been estimated to be between 3-4 cases for every 100,000 adults (Sant, Blood, 2010; Smith, Brit Journal of Cancer, 2011). The cause of underlying mutations is unknown for most cases of AML arising in adults, but AML is often associated with environmental factors (chemicals, radiation, tobacco, alkylating chemotherapy, retroviruses), myeloproliferative disorders, and Down syndrome (Sant, Blood, 2010; cancer.org).

U.S. Acute Myeloid Leukemia Cancer Incidence (NIH SEER)

Click to Enlarge

AML is caused by chromosomal abnormalities and mutations. These mutations interfere with the regulation of cellular growth and differentiation, allowing the leukemia cells to grow unfettered. These abnormal cellular clones suppress bone marrow activity, preventing normal hematologic processes. Patients can present with varying, sometimes nonspecific symptoms, including fever, weight loss, anemia, easy bruising, abnormal bleeding, or infections. AML is suspected when blood tests show increased circulating blast cells (immature myeloid cells), cytopenia (reduced number of mature blood cells), or if patients present with unexplained metabolic emergencies. AML is diagnosed by bone marrow aspirate and biopsy analysis (Cancer.org). AML is rapidly lethal if left untreated. With intensive treatment, 60-80% of young adults achieve complete remission and one-third are ultimately cured. However, increasing age, general health, and other comorbidities all impact how well patients tolerate chemotherapy and survival rates (Döhner, Blood, 2017).

Diagram showing the cells in which AML originates.

AML is generally treated with chemotherapy and hematopoietic stem cell transplant. Treatment typically starts with an induction phase of therapy, during which patients receive a combination of the drugs anthracycline and cytarabine. The goal of the induction phase is to achieve complete remission (the disappearance of detectable leukemia cells). Complete remission is achieved in 60-80% of younger adults and 40-60% of older adults (60 years and above). Following induction therapy, patients continue to receive cytarabine or another chemotherapy followed by hematopoietic cell transplantation (Döhner, Blood, 2017).

Treatment is not without risks. All treatment puts patients at increased risk for infections, and chemotherapies are toxic to many organ systems. For example, anthracycline is well known for its cardiotoxic effects and cytarabine can be toxic to the brain in high doses, leading to gait abnormalities. For some patients, treatment with the intent of complete remission may even be inadvisable due to their age, disabilities, coexisting medical problems or prior treatment (De Kouchkovsky, Blood Cancer J., 2016). Given these risks and low response rates, there is a need for more effective treatment strategies on the market to improve patient outcomes.

Cannabidiol (CBD) as an Adjunct to Standard of Care Treatment

Cannabinoids are a group of chemicals extracted from the cannabis plant. There is a growing body of research pointing toward the therapeutic potential of cannabinoids, especially cannabidiol (CBD), in cancer treatment. The anticancer effect seems to stem, in part, from activation of cannabinoid receptors on tumor cells. Activation of these receptors slows cancer cell growth, induces apoptosis, and inhibits neovascularization of tumors (Liu, Lett Drug Disc Des, 2006). The CB2 receptor has previously been shown to be overexpressed in several AML lines (Jordà, Blood, 2004), making it a potential target for CBD therapy. One group of researchers was able to demonstrate that CBD exposure to leukemia cells led to significant CB2 receptor-mediated decrease in the number of viable cells as well as the induction of apoptosis, both in vitro and in vivo (McKallip, Mol Pharmacol, 2006).

CBD treatment led to reduced tumor burden and apoptosis in vivo in a murine leukemia model (McKallip, Mol Pharmacol, 2006).

Click to Enlarge

However, the impact of cannabinoids does not appear to be limited to receptor responses alone. Cannabinoids appear to elicit cell-killing mechanisms even when the cannabinoid receptors are not present on target cells. In fact, anticancer activity, independent of cannabinoid receptors, has been seen in several leukemia cell types treated with cannabinoids (Powles, Blood, 2005). This receptor-independent anticancer activity is presumed to be due to the ability of cannabinoids to disrupt intracellular signaling pathways. (Liu, Curr Clin Pharm, 2010).

Merits of a Cannabinoid Combination Therapy

While there have been demonstrated benefits to the use of CBD as a monotherapy, recent research suggests that combination therapy with other chemotherapeutic drugs may be more advantageous, by targeting progression of the cancer at different levels and minimizing toxicities of these therapies relative to higher doses when used as monotherapies (Yasmin-Karim, Front Oncol, 2018).

For example, in one recent in vitro study by Scott, et al, researchers found that when cannabinoid monotherapy was used on cell lines of acute lymphocytic leukemia and promyelocytic leukemia (a subtype of AML), there was reduction in neoplastic cell counts by stopping the growth of the malignant cells through cytostatic mechanisms. However, when cannabinoids were combined, outcomes were improved when compared to any one compound alone (Scott, Anticancer Res, 2013). Another in vitro study demonstrated that the combination of cannabinoids with anti-leukemia drugs, especially cytarabine and vincristine, actually increased the rate of cancer cell apoptosis, instead of just halting its growth (Scott, Int J Onc, 2017).Given that cytarabine is the most common chemotherapy used for the treatment of AML, cannabinoids could be used as effective treatment adjuvants, especially in patients demonstrating resistance to treatment.

Another promising area of research in AML therapy is cholesterol epoxide hydrolase (ChEH)/antiestrogen binding site (AEBS) inhibitors. These inhibitors interfere with cholesterol biosynthesis and tumor cell growth, differentiation, death, and cancer progression. Researchers at the Soroka University Medical Center in Israel have been studying the interplay of combination therapy with ChEH/AEBS inhibitors and CBD in vitro, with encouraging results. In one study, the researchers showed that exposure to CBD alone leads to a reduction in the number of viable AML cells. However, when combined with DPPE, a selective ChEH/AEBS inhibitor, there was even more potent anticancer activity. A synergistic effect was also found when CBD was combined with the estrogen modulator clomiphene citrate in the reduction of viable leukemia cell lines. This effect was seen in both estrogen receptor positive and estrogen receptor negative cell lines, supporting the hypothesis that CBD and clomiphene work together independently of estrogen receptor involvement (WO2017072773A1).

Clinical Program

Jay Pharma is planning an open label exploratory Phase 2 clinical trial to assess the safety and efficacy of the combinations of nonsteroidal antiestrogens and cannabidiol in patients with AML. The primary endpoint will be the overall response rate of combination therapy clomiphene/DPPE and cannabidiol for patients with refractory or relapsed. This research has the potential to further our understanding of the pathogenesis of AML and improve therapeutic outcomes.